Recent advances in the diagnosis of childhood tuberculosis.

Children account for a major proportion of the global tuberculosis disease burden, especially in endemic areas. However, the accurate diagnosis of childhood tuberculosis remains a major challenge. This review provides an overview of the most important recent advances in the diagnosis of intrathoracic childhood tuberculosis: (1) symptom-based approaches, including symptom-based screening of exposed children and symptom-based diagnosis of active disease; (2) novel immune-based approaches, including T cell assays and novel antigen-based tests; and (3) bacteriological and molecular methods that are more rapid and/or less expensive than conventional culture techniques for tuberculosis diagnosis and/or drug-resistance testing. Recent advances have improved our ability to diagnose latent infection and active tuberculosis in children, but establishing a diagnosis of either latent infection or active disease in HIV-infected children remains a major challenge, particularly in high-burden settings. Although improved access to diagnosis and treatment is essential, ultimately the burden of childhood tuberculosis is determined by the level of epidemic control achieved in a particular community. Several recent initiatives, in particular the United Nations Millennium Developmental Goals, deal with the problem of poverty and disease in a holistic fashion, but global political commitment is required to support these key initiatives.     

New approaches and emerging technologies in the diagnosis of childhood tuberculosis

Childhood tuberculosis (TB) has long been neglected by TB control programmes, as children tend to develop sputum smear-negative disease and rarely contribute to disease transmission. However, children suffer severe TB-related morbidity and mortality in areas with endemic TB and carry a significant proportion of the global disease burden. Apart from improved control of the global TB epidemic, access to accurate diagnosis and effective treatment is essential to reduce the disease burden associated with childhood TB. Access to child friendly anti-TB treatment is improving, but establishing an accurate diagnosis remains a challenge. This review provides an overview of recent advances in the diagnosis of childhood TB, focusing on bacteriological, immunological, radiological and symptom-based approaches. It is possible to establish a fairly accurate diagnosis of either latent infection or active TB in immunocompetent children, even in resource-limited settings, but establishing an accurate diagnosis of TB in HIV-infected (immunocompromised) children remains a major challenge.     

Updated diagnosis and treatment of childhood tuberculosis

Background

Childhood tuberculosis (TB) accounts for a significant proportion of the global tuberculosis disease burden. However, current and previous efforts to develop better diagnostic, therapeutic, and preventive interventions have focused on TB in adults, and childhood TB has been relatively neglected. The purpose of this review is to provide an update on the diagnostic and therapeutic recommendations for childhood TB with an emphasis on intrathoracic disease.

Data sources

The literature from a range of sources was reviewed and synthesized to provide an overview of the contemporary approaches for the diagnosis and treatment of childhood TB.

Results

This review summarizes the clinical, radiological, bacteriological, and immunological approaches to diagnose TB infection and disease in children. In addition, we summarize the updated guidelines for the treatment of TB in children.

Conclusions

The development of better diagnostic and therapeutic methods for childhood TB remains a significant challenge. As the strategies for diagnosis and treatment of childhood TB continue to improve and the knowledge base increases, the implementation of these strategies will be crucial.     

Proposed management of childhood tuberculosis in low-incidence countries

The incidence of childhood tuberculosis continues to decline in central Europe, but due to migration from high incidence countries paediatricians will still be confronted with it. The management of childhood tuberculosis in low-incidence, high-income countries differs from most high-incidence countries. The primary measures for preventing the transmission of tuberculosis to children are the detection of adult source cases, detection of latent TB infection (LTBI) in children by history, tuberculin skin testing and, if necessary and recommended, interferon-gamma release assays. Children with LTBI should receive preventive therapy. The inclusion of tuberculosis in the differential diagnosis of unclear pulmonary and extrapulmonary disease remains important, and tuberculosis has to be managed according to international standards.     

T-cell-based diagnosis of neonatal multidrug-resistant latent tuberculosis infection

Young children exposed to tuberculosis have a high risk of progression to severe tuberculosis disease, but diagnosis of recent infection is hindered by the poor sensitivity of the tuberculin skin test. Whether new blood tests can detect latent infection in this vulnerable group is unknown because there is no gold standard. We monitored a tuberculin skin test-negative infant whose mother had infectious multidrug-resistant tuberculosis with enzyme-linked immunospot, a blood test that enumerates Mycobacterium tuberculosis-specific T cells. The enzyme-linked immunospot test became persistently positive by 6 months, and 18 months later the child developed active tuberculosis despite appropriate chemoprophylaxis. At this point, the magnitude of the enzyme-linked immunospot response increased >10-fold. Our findings demonstrate that this blood test detected latent infection with dormant, yet viable, bacilli and illustrate how enzyme-linked immunospot could improve diagnosis of childhood tuberculosis infection.     

Clinical practice

Childhood tuberculosis (TB) represents an important part of the disease burden, yet its diagnosis remains challenging. This review summarizes the clinical, radiological, and bacteriological approaches to diagnose TB infection and disease in children. Fever (possibly intermittent or low grade), weight loss or failure to thrive, and a persistent cough for >2 weeks are the most important clinical signs for pulmonary tuberculosis. Extra-pulmonary TB, which might occur in over 40% of the patients, can have in addition some specific clinical symptoms or signs. Chest radiographs provide important information in many patients and advanced imaging can be applied in case of (and should be restricted to) inconclusive diagnosis. The Mantoux test is positive in up to 70% of non-immunocompromised TB patients, whereas HIV co-infection or malnourishment results in a lower reactivity. Evidence of an adult TB index case is clue for diagnosis of childhood TB in low-endemic countries. Bacteriological confirmation remains difficult and is useful for doubtful cases or when drug resistance is suspected.     

Epidemiology and clinical management of tuberculosis in children in Canada

Although often regarded as a foreign disease, latent tuberculosis or tuberculosis disease will be encountered in many clinical situations by the Canadian child health practitioner. There are key differences between tuberculosis in children and adults. In the present article, the changing epidemiology of tuberculosis in children in Canada and around the world, the pathogenesis of infection, diagnostic tests, and clinical management of childhood latent tuberculosis and tuberculosis disease are reviewed.     

Tuberculosis in children and adolescents in the 1980s

Tuberculosis (TBC) continues to be a major health problem. Between January 1, 1980, and April 30, 1986, 211 children and adolescents presented with a positive tuberculin reaction or symptoms suggestive of tuberculosis. Active disease occurred in 35 (17%); 29 of these had primary infection, whereas 4 adolescents presented with cavitary pulmonary disease and 1 infant each had Pott's disease and cervical adenitis. The proportion of patients with active disease was greater in infants and toddlers; 2 of whom also had meningitis. Two children with active disease were infected with human immunodeficiency virus, 1 of whom died with cavitary tuberculosis. Only 43% of 211 patients were born in the United States. The ethnic distribution was Hispanic 45%, Oriental 30%, Black 18% and other 7%. Bacillus Calmette-Guérin vaccination was documented in 53 (25%) patients; 5 (9%) of these developed active disease. Despite vaccination and the availability of effective drugs, tuberculosis persists and appears to be increasing. Meeting the challenge of tuberculosis in the future will require more rapid diagnostic methods and recognition of the burden of infection in human immunodeficiency disease-infected children, together with revitalization of screening and follow-up programs, especially for toddlers and adolescents.     

Modern approach to the diagnosis and treatment of tuberculosis in children

Tuberculosis in children remains an important infectious disease in the United States, with 1261 cases reported in 1985. The percentage of extrapulmonary manifestations is increasing. Advances in the diagnosis and treatment of tuberculosis in children have lagged behind those in adults owing to diminished familiarity with the disease and difficulty in performing clinical studies in children. Tuberculosis in the United States now occurs mainly in clusters of high-risk people, such as the foreign born, Hispanics, blacks, Native Americans, and the impoverished. In general, the diagnosis of tuberculosis is epidemiologic, supported by the chest roentgenogram, skin test, and, most important, contact tracing. As the rate of drug-resistant tuberculosis increases, greater effort should be made to obtain cultures. New advances, such as DNA probes and serodiagnosis, may improve diagnostic accuracy, especially for extrapulmonary tuberculosis. Noncompliance is the major problem in treating tuberculosis, and greater effort should be directed toward novel treatment approaches in children, such as twice-weekly supervised therapy and shorter, more intense durations of therapy.     

The diagnosis of tuberculosis

Childhood tuberculosis accounts for a significant proportion of the global tuberculosis disease burden. However, tuberculosis in children is difficult to diagnose, because disease tends to be paucibacillary and sputum samples are often not easy to obtain. The diagnosis of tuberculosis in children is traditionally based on chest radiography, tuberculin skin testing, and mycobacterial staining/culture from appropriate samples. Newer diagnostic strategies have included improved bacteriologic and molecular methods, as well as new methods for sample collection from children. Recently, immune-based diagnostics, such as the interferon-gamma release assays, have been introduced for clinical use. These tests do not offer substantial improvements in sensitivity over tuberculin skin testing for the diagnosis of active disease but may be useful in excluding false-positive tuberculin skin tests. Further research is needed to develop better diagnostic tests for tuberculosis in children.     

Non-pulmonary tuberculosis

Tuberculosis (TB) is a serious disease of global importance, with a rising incidence in the developed world in recent years. Tuberculous lymphadenitis, tuberculous meningitis, osteoarticular tuberculosis and miliary tuberculosis are some of the more well-recognised manifestations of non-pulmonary TB in childhood. The diagnosis of non-pulmonary TB poses a particular challenge for clinicians because of the protean ways in which the disease presents. The omission of tuberculosis from the differential diagnosis of patients with obscure illnesses and the relatively insensitive bacteriological methods for detecting Mycobacterium tuberculosis add to the complexity of the problem. A high index of suspicion is required in order to avoid delays in diagnosis which may influence treatment outcome. The advent of DNA amplification techniques such as the polymerase chain reaction may herald a promising new era in the prompt and accurate management of extrapulmonary tuberculosis.     

Global paediatric pulmonology: out of Africa

Respiratory illness is the major cause of mortality and morbidity in African children. The spectrum of disease includes acute and chronic respiratory illness. As a result of the HIV epidemic currently occurring in sub-Saharan Africa, HIV-associated acute and chronic respiratory disease has emerged as a major factor in the epidemiology of childhood respiratory illness. Pneumonia is the leading causes of childhood mortality responsible for approximately 21% of deaths in African children under five years of age each year. The HIV pandemic has increased the incidence, severity and pneumonia mortality in African children. Pulmonary tuberculosis (TB) is an important cause of morbidity and death. Globally, the highest TB incidence rates occur in sub-Saharan African countries; many of these countries are also experiencing a dual HIV epidemic, resulting in an exponential increase in TB cases. The burden of childhood respiratory illness has necessitated novel and improved ways of diagnosis, treatment and prevention, particularly in the context of limited resources. Improved diagnosis, treatment and prevention of pneumonia have been a research focus, particularly in HIV-infected children. African studies have provided information on the epidemiology, aetiology and outcome from pneumonia in HIV-infected and uninfected children. The efficacy of trimethoprim-sulphamethoxazole prophylaxis in reducing mortality and morbidity in HIV-infected African children was shown in the only randomized controlled trial. Two large studies have shown the efficacy of the pneumococcal conjugate vaccine in an African context. Regarding TB, areas of research include diagnostic studies and improved preventative strategies. Promising diagnostic studies for childhood TB include the use of sputum induction, PCR techniques and blood interferon assays. The immune reconstitution inflammatory syndrome (IRIS) has emerged as a new clinical entity in HIV-infected children with TB associated with use of antiretroviral therapy. New preventative strategies for TB include novel vaccines and primary prophylaxis. Available, effective interventions for prevention and treatment of childhood respiratory disease exist; the challenge is to achieve widespread implementation and high coverage rates in African countries. Greater access to newer vaccines and, in HIV-infected children, to anti-retroviral therapy and prophylaxis is necessary to further reduce the burden of childhood respiratory illness in Africa.     

Current challenges in lower respiratory infections in children

PURPOSE OF REVIEW: Lower respiratory infections threaten the health of children worldwide. Streptococcus pneumoniae remains the most common bacterial cause of lower respiratory infection in children, whereas viral pathogens dominate as a more common cause of lower respiratory infection illness in infants and children overall. The diagnosis and clinical management of lower respiratory infections pose challenges to pediatric health providers as new technology is developed and new pathogens emerge in the spectrum of clinical disease. RECENT FINDINGS: Human metapneumovirus is now recognized as a cause of lower respiratory infection disease in children, and coronavirus has been linked to epidemics of severe acute respiratory syndrome. Respiratory syncytial virus continues to be a major source of viral lower respiratory infection illness in children and can lead to childhood asthma. Treatment for respiratory syncytial virus bronchiolitis depends largely on the severity of disease and the course of clinical symptoms. The diagnosis of bacterial lower respiratory infection disease remains a clinical challenge, but new methods to detect S. pneumoniae, or Chlamydia pneumoniae and Mycoplasma pneumoniae may facilitate the clinical management of these illnesses. As immunization against S. pneumoniae becomes more widely used, the complications of bacterial lower respiratory infections will diminish markedly. SUMMARY: Future progress in the clinical management of lower respiratory infection diseases will entail improved methods of early diagnosis, broader options for treatment, and better defined clinical parameters for triage and follow-up of children with lower respiratory infections.     

结核菌素皮试和全血γ干扰素测定试验的儿童结核感染诊断应用研究

目的 评价结核菌素（PPD）皮试和全血γ干扰素（IFN-γ）测定试验诊断儿童结核病的准确性。方法 选择2006年7月至2010年4月首都医科大学附属北京儿童医院住院临床诊断结核和呼吸系统疾病的患儿为研究对象。根据患儿所暴露的结核感染危险因素分为5组：A组：无结核病密切接触史的非结核病的呼吸系统疾病患儿;B组：有活动性结核病患者密切接触史的非结核病的呼吸系统疾病患儿;C组：无结核病密切接触史的临床诊断结核病患儿;D组：有活动性结核病患者密切接触史的临床诊断结核病患儿;E组：病原学或病理学确诊的活动性结核病患儿。患儿于入院当日行PPD皮试,入院后1~7 d采集外周静脉血行全血IFN-γ测定。以敏感度、特异度、阴性预测值、阳性预测值和似然比评价PPD皮试和全血IFN-γ测定对结核病的诊断价值。结果 125例患儿进入分析。A组40例,B组11例,C组29例,D组27例,E组18例。①PPD皮试取硬结≥10 mm为阳性判断标准时,诊断结核病的敏感度为77.0%,特异度为70.6%;取硬结≥15 mm为阳性判断标准时,诊断结核病的敏感度为50.0%、特异度为80.2%;全血IFN-γ测定的敏感度为85.1%、特异度为94.1%。②PPD皮试取硬结≥10 mm为阳性判断标准诊断结核病时,<3岁患儿PPD皮试的敏感度和特异度均显著低于≥3岁患儿,城区和郊区患儿的敏感度和特异度接近;全血IFN-γ测定诊断结核病的敏感度和特异度在不同年龄、居住地间差异无统计学意义。③全血IFN-γ测定阳性率与结核感染暴露因素的相关性优于PPD皮试（取硬结≥10或15 mm为阳性判断标准时）。结论 潜伏结核感染筛查时以硬结≥15 mm作为PPD皮试阳性判断标准,可提高诊断的特异度;临床疑似结核病的诊断以硬结≥10 mm作为PPD皮试阳性判断标准,可提高诊断的敏感度。全血IFN-γ测定诊断结核病的敏感度和特异度均较好。     

Tuberkulose

Background

Childhood tuberculosis is a chronic infectious disease caused by pathogenic bacteria of the Mycobacterium tuberculosis complex genus. Tuberculosis has become rare in most developed countries during recent decades. In contrast, according to worldwide incidence rates, tuberculosis is still among the most frequent and deadly infectious diseases. In Germany, ‘imported’ tuberculosis cases from countries with high disease incidence are important, but the majority of cases occur in children born in Germany. Low case frequencies as well as lost knowledge about tuberculosis symptoms and diagnosis pose the hazard of nonobservance.

Diagnosis

Diagnosis of tuberculosis in childhood is particularly difficult because of often unclear symptomatology. Therefore, reasonable usage of available tools (i.e., immunodiagnostics, imaging techniques, pathogen detection) is crucial for diagnosis.

Aim of this article

This review focuses on immunodiagnostic methods and discusses limitations of available tests. Finally, it summarizes how recent scientific findings on tuberculosis pathogenesis and latent Mycobacterium tuberculosis infection may lead to novel diagnostic approaches and predictive biomarkers for tuberculosis treatment efficacy.     

Actualización del tratamiento de la tuberculosis en niños

Tuberculosis (TB) is the most important infectious disease all over the world, with a high morbidity and mortality. Pediatric tuberculosis has been a neglected epidemic, due to the difficulties in assessing its global impact, reduced incidence and lower infectivity compared to adults. In 2015, the WHO reported 1 million cases of paediatric TB and 169,000 deaths. In Europe, the emergence of MDR TB is a major concern, representing 16% of the new diagnosis in Eastern Europe. In 2014, it was estimated that about 219,000 children were infected by MDR-TB-strains in Europe, and 2,120 developed the disease. Spain is the Western European country with more paediatric cases, with an incidence 4.3/100,000 inhabitants in 2014. Paediatric tuberculosis mortality in Spain is rare, but extra-pulmonary disease is associated with significant complications. The prevalence of paediatric drug resistant TB in Spain is over 4%, higher than the estimated incidence in adult population, representing mayor difficulties for therapeutic intervention. These data reveal that paediatric TB is still a Public Health priority in our country.The difficulties in diagnosis and the lack of optimal paediatric drug formulations are the major challenges for controlling the childhood's tuberculosis epidemic. A group of national paeditric TB experts has reviewed the international guidelines and the most recent evidences, and has established new recommendations for the management of paediatric TB contacts, latent infection and active TB disease, especially focused in drug resistant cases. This document replaces the former national guidelines from the Spanish Society for Pediatric Infectios Diseases, although the prior recommendations on the diagnosis remain valid.     

Tuberculosis control in India: Why are we failing?

In spite of being the pioneer-leader of research into epidemiology and prevention of tuberculosis among low-income countries, India has the highest population-based burden of tuberculosis among all nations. Children with latent tuberculosis are the pool from which adult pulmonary tuberculosis emerges many years later. In the absence of primary prevention of infection by BCG, sociologic/behavioral interventions must be applied to reduce air-borne transmission. In addition to maximizing passive surveillance of adult disease, pediatric tuberculosis must also be brought under surveillance. Those with latent tuberculosis must be detected and treated to remove them from the pool. Epidemiologically, the realistic monitoring method of tuberculosis control trajectory is documenting progressive reduction of the short incubation period pediatric disease through surveillance, and not the reduction of long incubation period adult pulmonary tuberculosis. Application of scientific tools for the detection and management of pediatric tuberculosis infection — latent and active — holds the key to effective tuberculosis control.     

The Use of Diagnostic Systems for Tuberculosis in Children

Effective management of tuberculosis (TB) in children and important data of disease burden continue to rely on a clinical approach to diagnosis, as diagnosis of childhood TB is not confirmed in the majority. Many diagnostic scoring systems have been developed to aid with diagnosis. This article reviews the use and evaluation of these approaches. The diagnostic systems are often closely related and all rely on the well-known clinical features associated with TB disease in children. The scoring systems are not well validated and validation is limited by the lack of a gold standard for comparison. When they have been validated, some systems perform reasonably well but may bias to identify the most obvious clinical cases. They perform less well in important sub-groups that pose the greatest diagnostic challenge and are at greatest risk for poor outcome, such as the young, malnourished or HIV-infected. There is marked variation in performance between these diagnostic approaches. The better validated systems may have a role as a screening tool in some settings, but this would need careful consideration as to the most useful and safest approach. More attention is being given to improving diagnosis and management of child TB, including within National TB Programmes. Research with new diagnostics should include children so that there is less reliance on clinical features alone. However, the clinical approach will continue to be relevant and so it is important to strive to improve the diagnostic approach to TB in children, and to validate the approach in different settings.     

Childhood turberculosis: reflections from the front line

Tuberculosis is a major cause of childhood morbidity and mortality in high-burden settings, particularly in the third-world settings. Effective intervention in these resource-limited areas requires a clear focus on high-risk groups. Children rarely contribute to disease transmission, but their disease is the direct result of continued transmission within the community. The burden of childhood tuberculosis reflects the level of epidemiological control achieved within the adult population. Adequate diagnosis and treatment should be available for every child, but reducing the burden of childhood disease requires a concerted effort to contain the epidemic.     

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.