Anneke C. Hesseling

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.

A Refined Symptom-Based Approach to Diagnose Pulmonary Tuberculosis in Children

BACKGROUND. Tuberculosis control programs place an almost exclusive emphasis on adults with sputum smear-positive tuberculosis, because they are most infectious. However, children contribute a significant proportion of the global tuberculosis caseload and experience considerable tuberculosis-related morbidity and mortality, but few children in endemic areas have access to antituberculosis treatment. The diagnostic difficulty experienced in endemic areas with limited resources has been identified as a major factor contributing to poor treatment access. In general, there is a sense of scepticism regarding the potential value of symptom-based diagnostic approaches, because current clinical diagnostic approaches are often poorly validated. The natural history of childhood tuberculosis demonstrates that symptoms may offer good diagnostic value if they are well defined and if appropriate risk stratification is applied. This study aimed to determine the value of well-defined symptoms to diagnose childhood pulmonary tuberculosis in a tuberculosis-endemic area. METHODS. A prospective, community-based study was conducted in Cape Town, South Africa. Specific well-defined symptoms were documented in all children <13 years of age reporting a persistent, nonremitting cough of >2 weeks duration; study participants were thoroughly evaluated for tuberculosis. In addition, all of the children who received antituberculosis treatment during the study period were reviewed by the investigator, irrespective of study inclusion. This concurrent disease surveillance provided a comprehensive overview of all of the childhood tuberculosis cases, allowing accurate assessment of the possible disadvantages associated with this symptom-based diagnostic approach. In the absence of an acceptable gold standard test, optimal case definition is an important consideration. Children were categorized as “bacteriologically confirmed tuberculosis,” “radiologically certain tuberculosis,” “probable tuberculosis,” or “not tuberculosis.” Bacteriologically confirmed tuberculosis was defined as the presence of acid-fast bacilli on sputum microscopy and/or Mycobacterium tuberculosis cultured from a respiratory specimen. Radiologically certain tuberculosis was defined as agreement between both independent experts that the chest radiograph indicated certain tuberculosis in the absence of bacteriologic confirmation. Probable tuberculosis was defined as the presence of suggestive radiologic signs and good clinical response to antituberculosis treatment in the absence of bacteriologic confirmation or radiologic certainty. Good clinical response was defined as complete symptom resolution and weight gain of ≥10% of body weight at diagnosis, within 3 months of starting antituberculosis treatment. Not tuberculosis was defined as spontaneous symptom resolution or no response to antituberculosis therapy in the absence of bacteriologic confirmation or radiologic signs suggestive of tuberculosis. Pulmonary tuberculosis was defined as a symptomatic child with: (1) bacteriologically confirmed tuberculosis, (2) radiologically confirmed tuberculosis, or (3) probable tuberculosis (as defined), excluding isolated pleural effusion. RESULTS. In total, 1024 children were referred for evaluation. Resolving symptoms were reported in 596 children (58.2%); 428 (41.8%) children with persistent, nonremitting symptoms at evaluation were investigated for tuberculosis. Pulmonary tuberculosis was diagnosed in 197 children; 96 were categorized as bacteriologically confirmed tuberculosis, 75 as radiologically certain tuberculosis, and 26 as probable tuberculosis. Combining a persistent nonremitting cough of >2 weeks duration, documented failure to thrive (in the preceding 3 months), and fatigue provided reasonable diagnostic accuracy in HIV-uninfected children (sensitivity: 62.6%; specificity: 89.8%; positive predictive value: 83.6%); the performance was better in the low-risk group (≥3 years; sensitivity: 82.3%; specificity: 90.2%; positive predictive value: 82.3%) than in the high-risk group (<3 years; sensitivity: 51.8%; specificity: 92.5%; positive predictive value: 90.1%). In children with an uncertain diagnosis at presentation, clinical follow-up was a valuable diagnostic tool that further improved diagnostic accuracy, particularly in the low-risk group. Symptom-based approaches offered little diagnostic value in HIV-infected children. Three (15%) of the 20 HIV-infected children diagnosed with pulmonary tuberculosis failed to report symptoms of sufficient duration to warrant study inclusion, whereas 25% reported persistent, nonremitting symptoms in the absence of tuberculosis. In addition, the tuberculin skin test was positive in <20% of HIV-infected children diagnosed with pulmonary tuberculosis. DISCUSSION. The combined presence of 3 well-defined symptoms at presentation (persistent, nonremitting cough of >2 weeks duration; objective weight loss [documented failure to thrive] during the preceding 3 months; and reported fatigue) provided good diagnostic accuracy in HIV-uninfected children ≥3 years of age, with clinical follow-up providing additional value. The approach performed less well in children <3 years. However, the presence of a persistent, nonremitting cough together with documented failure to thrive still provided a fairly accurate diagnosis (sensitivity: 68.3%; specificity: 80.1%; positive predictive value: 82.1%), illustrating the importance of regular weight monitoring in young children. Clinical follow-up also offered additional diagnostic value, but caution is required, because very young children have an increased risk of rapid disease progression. The approach performed poorly in HIV-infected children. Recent household contact with an adult index case seemed to provide more diagnostic value than a positive tuberculin skin test, but novel T-cell-based assays may offer the only real improvement in sensitivity to diagnose M tuberculosis infection in HIV-infected children. The variable diagnostic value offered by this symptom-based diagnostic approach illustrates the importance of risk stratification, as demonstrated by the fact that 11 (91.7%) of 12 children with severe disease manifestations who failed to meet the entry criteria were <3 years of age or HIV infected. Particular emphasis should be placed on the provision of preventive chemotherapy after documented exposure and/or infection in these high-risk children. Study limitations include the small number of HIV-infected children, but on the positive side, the large number of HIV-uninfected children permitted adequate evaluation in this important group. It is often forgotten that HIV-uninfected children constitute the majority of child tuberculosis cases, even in settings where HIV is endemic. This study demonstrates the importance of ascertaining a childs HIV status before symptom-based diagnosis is attempted. Because children were recruited at both the clinic and hospital level, some selection bias may have been introduced; however, the only significant difference between the 2 groups was the proportion of HIV-infected children. Pulmonary tuberculosis was diagnosed with different levels of certainty, but no significant differences were recorded between these groups. CONCLUSIONS. Pulmonary tuberculosis can be diagnosed with a reasonable degree of accuracy in HIV-uninfected children using a simple symptom-based approach. This offers the exciting prospect of improving treatment access for children, particularly in resource-limited settings where current access to antituberculosis treatment is poor.

Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis.

BACKGROUNDnChildren infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis (TB) and can therefore benefit from preventive therapy.nnnOBJECTIVEnTo assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) in the diagnosis of TB infection and disease in children.nnnMETHODSnThirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] and T-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB, compared to children where TB was excluded.nnnRESULTSnTwo small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immunodeficiency virus infected children.nnnCONCLUSIONSnAvailable data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.BACKGROUNDnChildren infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis(TB) and can therefore benefit from preventive therapy.nnnOBJECTIVEnTo assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST)in the diagnosis of TB infection and disease in children.nnnMETHODSnThirty-three studies were included, assessing commercial IGRAs (QuantiFERON®-TB [QFT] andT-SPOT.®TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB,compared to children where TB was excluded.nnnRESULTSnTwo small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure-categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immuno deficiency virus infected children.nnnCONCLUSIONSnAvailable data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Evaluation of tuberculosis diagnostics in children: 2. Methodological issues for conducting and reporting research evaluations of tuberculosis diagnostics for intrathoracic tuberculosis in children. Consensus from an expert panel.

Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.

Well defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis

Background: The diagnosis of childhood pulmonary tuberculosis presents a major challenge as symptoms traditionally associated with tuberculosis are extremely common in children from endemic areas. The natural history of tuberculosis in children shows that progressive disease is associated with symptoms which have a persistent, non-remitting character. The aims of this study were to investigate whether improved symptom definition is possible in a clinical setting, and whether use of these well defined symptoms has improved value in the diagnosis of childhood pulmonary tuberculosis. Methods: A prospective, community based study was conducted in two suburbs of Cape Town, South Africa. All children (<13 years) presenting to the local community clinic with a cough of >2 weeks duration, were referred to the investigator. Parents completed a symptom based questionnaire, whereafter reported symptoms were characterised in a standard fashion. Results: Of the 151 children enrolled, 21 (15.6%) reported symptoms with a persistent, non-remitting character. Tuberculosis was diagnosed in 16 (10.5%) children, all of whom reported these symptom characteristics. A persistent, non-remitting cough was reported in 15/16 (93.8%) children with tuberculosis and in 2/135 (1.5%) children without tuberculosis, indicating a specificity of 98.5% (135/137). Persistent fatigue of recent onset was also sensitive (13/16, 81.3%) and specific (134/135, 99.3%). Persistent fever and/or chest pain were exclusively reported in children with tuberculosis, but were present in only 4/16 (25.0%) children with tuberculosis. Conclusion: The use of well defined symptoms is feasible, even in resource limited settings, and may offer significantly improved value in the diagnosis of childhood pulmonary tuberculosis.

Outcome of HIV-infected children with culture-confirmed tuberculosis

Background: Tuberculosis (TB) is an important disease in human immunodeficiency virus (HIV) infected children living in regions where TB is endemic. There are limited data on the outcome of culture confirmed TB in HIV infected children. Aims and Methods: To describe the outcome on TB therapy and overall mortality in HIV infected children with culture confirmed TB through a retrospective cohort study. Results: Eighty seven children, median age 24 months, contributed to 93 TB episodes; six children had two confirmed episodes. Pulmonary disease (PTB) was present in 71 episodes (76.3%), extrapulmonary disease (EPTB) in 43 (46.2%), and of these, both PTB and EPTB were present in 21 (22.6%). There was cure based on bacteriological and/or radiological criteria in 54 episodes (58.1%). Eighteen children died during TB therapy and there were a total of 34 deaths (39.1%). In univariate analysis (nu200a=u200a87 patients), severe malnutrition, age ⩽1 year, and a negative tuberculin skin test were significant risk factors for death during TB therapy. In multivariate survival analysis (nu200a=u200a87 patients), HIV disease category, severe malnutrition at diagnosis, and lack of cure at the end of TB therapy were significantly associated with overall mortality. Conclusion: In the absence of antiretroviral therapy, HIV infected children with confirmed TB have poor outcomes on antituberculosis therapy and are at high risk of death during and after completion of antituberculosis therapy, especially due to non-TB related causes. There is an urgent need to optimise and monitor antituberculosis therapy in HIV infected children and to improve access to TB and other preventative therapy.

The prevalence of symptoms associated with pulmonary tuberculosis in randomly selected children from a high burden community

Background: Diagnosis of childhood tuberculosis is problematic and symptom based diagnostic approaches are often promoted in high burden settings. This study aimed (i) to document the prevalence of symptoms associated with tuberculosis among randomly selected children living in a high burden community, and (ii) to compare the prevalence of these symptoms in children without tuberculosis to those in children with newly diagnosed tuberculosis. Methods: A cross sectional, community based survey was performed on a 15% random sample of residential addresses. A symptom based questionnaire and tuberculin skin test (TST) were completed in all children. Chest radiographs were performed according to South African National Tuberculosis Control Program guidelines. Results: Results were available in 1415 children of whom 451 (31.9%) were TST positive. Tuberculosis was diagnosed in 18 (1.3%) children. Of the 1397 children without tuberculosis, 253 (26.4%) reported a cough during the preceding 3 months. Comparison of individual symptoms (cough, dyspnoea, chest pain, haemoptysis, anorexia, weight loss, fatigue, fever, night sweats) in children with and without tuberculosis revealed that only weight loss differed significantly (ORu200a=u200a4.5, 95% CI 1.5 to 12.3), while the combination of cough and weight loss was most significant (ORu200a=u200a5.4, 95% CI 1.7 to 16.9). Children with newly diagnosed tuberculosis reported no symptoms in 50% of cases. Conclusion: Children from this high burden community frequently reported symptoms associated with tuberculosis. These symptoms had limited value to differentiate children diagnosed with tuberculosis from those without tuberculosis. Improved case definitions and symptom characterisation are required when evaluating the diagnostic value of symptoms.

Short-Term Reproducibility of a Commercial Interferon Gamma Release Assay

ABSTRACT Interferon gamma release assays (IGRAs) have been shown to be sensitive and highly specific for the detection of immune memory against Mycobacterium tuberculosis. Little is known about the reproducibility and within-person variability of these assays. Various aspects of short-term reproducibility of a commercial IGRA, the QuantiFERON-TB Gold In-Tube (QFT-IT) assay, were assessed. The QFT-IT assay was performed twice within 3 days in 27 health care workers in Cape Town, South Africa. Two sets of tests were performed by different operators on day 1, and one set was performed on day 3. Aspects such as interoperator, intraoperator, day-to-day variability, and test-retest variability as well as different the storage methods of plasma were investigated. Seventeen of 27 (63%) of participants had at least one positive QFT-IT text; six had discordant results. The agreement of all aspects studied was high, with kappa values between 0.82 and 1.00 for dichotomous measures, and interclass correlations (ICC) of 0.809 to 0.965 were observed for continuous gamma interferon (IFN-γ) measures. The variability of the magnitude of response was highest comparing measures obtained from individuals on different days (ICC of 0.809). The magnitude of the IFN-γ responses between assays performed for individual participants was variable, with ranges from 0.03 to 11 IU/ml, resulting is discordant results for five participants. The results indicate that the QFT-IT assay is a robust and highly reproducible assay. Considerable intraindividual variability occurs in the magnitude of IFN-γ responses, which may influence the interpretation of serial measures.

A proposed comprehensive classification of tuberculosis disease severity in children

Background: Tuberculosis (TB) in children has conventionally been classified as pulmonary TB (PTB) and extrapulmonary TB (EPTB) disease, including disseminated TB (TB meningitis and miliary disease). There is no existing approach that comprehensively characterizes the spectrum and severity of pediatric TB. This limits accurate classification of patients and comparison across cohorts. Aims: To develop a classification of pediatric TB that reflects the spectrum and severity of clinical disease better than currently available approaches. Methods: We propose a framework for the standard classification of TB disease severity in children. From a literature search, the following sources of information were used: clinical data, bacteriologic, histopathologic, and imaging data (including information from chest radiography, computerized tomography, and bronchoscopy). Each individual disease entity was systematically considered. Based on the extent and the presence of complications, each entity was then classified as “severe” or “nonsevere.” As an initial application, we compared the proposed classification with the convention (PTB, EPTB) in a cohort of HIV-infected and -uninfected infants with culture-confirmed TB. Agreement between the 2 systems was poor. Conclusions: The proposed comprehensive disease classification system may more accurately reflect the clinical TB disease spectrum in children, is relevant to clinical management, and may be valuable to inform research on diagnostic tools and TB treatment strategies in children. Prospective studies are required to evaluate this approach in representative pediatric populations, correlating TB disease severity with diagnostic yield, treatment response, and application in existing and novel treatment strategies.