Difficultés du diagnostic de la tuberculose chez l’enfant : intérêt du test QuantiFÉRON TB Gold® In-Tube

Diagnosis of childhood tuberculosis (TB), active TB or latent tuberculosis infection (LTBI), is complicated by uncommon clinical, radiological and bacteriological features. The tuberculin skin test (TST) is imperfect: difficulty of the intradermal injection for the child, lack of sensibility and specificity. The stop of the systematic inoculation by the BCG since July 2007, in France, could lead to an increase of the incidence of the childhood TB. It is urgent to find new diagnostic tools: sensitive, specific, fast, of objective reading and little expensive. Interferon-γ assays could be useful but the data are still insufficient in paediatrics and sometimes contradictory. A prospective study which compared the usefulness of QuantiFERON TB Gold^® In-Tube (QFT-IT) assay with TST to detect LTBI or active disease in 51 children was realised in University Hospital of Nancy. This allowed us to confirm interest of QFT-IT; however, surprisingly, very discordant QFT-IT and TST results were obtained (only five children were QFT-IT+/TST+). A high number (14%) of indeterminate QFT-IT occurred, without explanation by pre-analytical or clinical parameters. Further studies are needed to demonstrate the usefulness of this assay in diagnosing LTBI and particularly active TB in children.     

结核分枝杆菌特异性效应T细胞斑点数鉴别儿童活动性结核病与潜伏结核感染的价值

目的 通过γ干扰素释放试验探讨结核分枝杆菌特异性效应T细胞斑点数（简称T细胞斑点数）鉴别儿童活动性结核病（TB）与潜伏结核感染（LTBI）的价值。方法 纳入T细胞斑点试验（T.SPOT.TB）阳性且未经过抗结核治疗的93例活动性TB（重症TB 27例,非重症TB 66例）和47例LTBI儿童,根据T.SPOT.TB结果对T细胞斑点数进行比较分析。结果 活动性TB组T细胞斑点数中位数84（6～710）显著高于LTBI组17（6～316）,P=0.000;非重症TB患儿的T细胞斑点数中位数为99（6～710）,显著高于重症TB的44（6～268）,P=0.011,也显著高于LTBI组17（6～316）,P=0.000;重症TB儿童T细胞斑点数中位数高于LTBI组儿童（44 vs 17）,但差异无统计学意义（P=0.084）,T细胞斑点数分布在活动性TB、重症TB、非重症TB和LTBI之间均有较大范围重叠。受试者工作特征曲线分析显示以T细胞斑点数43.5作为区分活动性TB与LTBI的最佳界值,其敏感度与特异度分别为69.9%和70.2%。结论 T细胞斑点数在活动性TB尤其是非重症TB患儿显著高于LTBI儿童;T细胞斑点数的数量可反映体内的结核分枝杆菌负荷,但不能用于区分儿童活动性TB与LTBI。     

Global aspects of tuberculosis in children

Tuberculosis (TB) in children reflects the prevalence of the disease in adults as well as current transmission rates. Africa and South-east Asia have the largest number of tuberculosis cases and the situation there has been worsened by the HIV epidemic. Children born to HIV-infected parents, whether infected or not, are at high risk of developing tuberculosis because of the increased risk of exposure to the disease. Tuberculosis is more common among the disadvantaged and vulnerable groups in each society and the impact of overcrowding, under-nutrition and poverty is particularly severe on children. Recent studies have documented the increase in the occurrence of tuberculosis in children, both in developed and developing countries. The peak age of notification of tuberculosis decreases as the incidence of the disease increases in the region. Tuberculosis infection can progress rapidly to disease, particularly in infancy and early childhood. Most of the morbidity occurs in the first few years after infection. Recently infected children and those with large tuberculin reaction (>18 mm) are at increased risk for progression and should be followed closely. Mortality from tuberculosis is also highest in early childhood, mainly due to disseminated forms like meningeal and miliary tuberculosis.Tuberculosis can be controlled either by preventing the infection from occurring or by treating early infection after it has occurred. An efficient tuberculosis control program with early detection of infectious adults and their cure is the best long-term approach to the reduction of TB disease in children. The DOTS strategy advocated by the WHO has the potential to have a significant impact on the epidemiology of tuberculosis by achieving high cure rates and thereby decreasing community transmission. BCG vaccination, through effective against disseminated forms of the disease in childhood, has very little impact on adult forms of the disease. Chemoprophylaxis or preventive therapy is effective, but difficult to implement on a mass scale and is only recommended for special high-risk groups in developing countries.     

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.     

Changing Trends in Childhood Tuberculosis

Several changes have been observed in the epidemiology, clinical manifestations, diagnostic modalities and treatment of tuberculosis. Emergence of HIV epidemic and drug resistance have posed significant challenges. With increase in the number of diseased adults and spread of HIV infection, the infection rates in children are likely to increase. It is estimated that in developing countries, the annual risk of tuberculosis infection in children is 2.5%. Nearly 8–20% of the deaths caused by tuberculosis occur in children. Extra pulmonary tuberculosis has increased over last two decades. HIV infected children are at an increased risk of tuberculosis, particularly disseminated disease. In last two decades, drug resistant tuberculosis has increased gradually with emergence of MDR and XDR-TB. The rate of drug resistance to any drug varied from 20% to 80% in different geographic regions. Significant changes have occurred in TB diagnostics. Various diagnostic techniques such as flourescence LED microscopy, improved culture techniques, antigen detection, nucleic acid amplification, line probe assays and IGRAs have been developed and evaluated to improve diagnosis of childhood tuberculosis. Serodiagnosis is an attractive investigation but till date none of the tests have desirable sensitivity and specificity. Tests based on nucleic acid amplification are a promising advance but relatively less experience in children, need for technical expertise and high cost are limiting factors for their use in children with tuberculosis. Short-course chemotherapy for childhood tuberculosis is well established. Directly observed treatment strategy (DOTS) have shown encouraging result. DOTS plus strategy has been introduced for MDR TB.     

New concepts in childhood tuberculosis

PURPOSE OF REVIEW: Childhood tuberculosis has long been neglected in international tuberculosis control efforts. There are, however, many opportunities to prevent childhood tuberculosis that are not being fully employed. RECENT FINDINGS: Several papers have been published to emphasize the unique nature of childhood tuberculosis and improve tuberculosis control in children. Treatment regimens have been improved and refined. Clinical and radiographic methods have been standardized. While new diagnostic tests are greatly needed, it is also apparent that any new tests--such as the interferon release assays--will need to be studied specifically in infants and children or there is a risk they may be misapplied. The areas of greatest need for research and clinical utility remain better diagnostic tests for tuberculosis infection and disease; shorter and more effective regimens for treating tuberculosis infection; better integration of children into standard tuberculosis control practices; a better understanding of the interaction of human immunodeficiency virus infection and tuberculosis in children; detection and treatment of drug-resistant tuberculosis in children; and a more effective vaccine. SUMMARY: True progress will require a rethinking of basic tuberculosis control with a commitment to address problems specific to childhood tuberculosis.     

儿童结核病流行病学及诊治现状

2014年, 全球共报告35.9万例儿童（0～14岁）结核病,占登记报告结核病病例的6.5%。2013年我国研究数据显示,不同结核病疫情地区5～15岁儿童的结核菌素试验（PPD）阳性率为8.09%～21.26%（≥10 mm）。2015年,全国共报告儿童肺结核患者6861例,发病率为3.03/10万。2014年,全国0～14岁儿童结核病死亡率为0.12/10万。儿童结核病诊断要基于对接触史、临床检查和相关检查等证据的全面评估。儿童结核病治疗原则与成人相同。目前国务院下发了《“十三五”全国结核病防治规划》,提出要完善儿童结核病的防治措施,对儿科医生开展结核病防治技术培训,规范儿童结核病的诊断和治疗服务。     

Tuberkulose im Kindesalter

In Germany, the incidence of childhood tuberculosis (Tb) continues to decline. Nevertheless, pediatricians are still be confronted with Tb due to migration from high incidence countries. Measures are needed to prevent the revival of Tb in Germany. This mainly involves the detection and treatment of latent Tb-infection by infection history, tuberculin-skin testing and, if necessary, interferon-gamma assays. The inclusion of Tb in the differential diagnosis of unclear lung disease is therefore important. Active disease has to be treated by combined chemotherapy as recommended. On the other hand, there seems to be an increase in infections with non-tuberculous mycobacteria (NTM). The therapy in NTM-infection differs from that in Tb, therefore differentiation between Tb and NTM-infections, for example in cervical lymphadenopathy, is important.     

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??In 2014??a total of 359 000 cases of tuberculosis??0-14 years old?? in children were reported worldwide??accounting for 6.5 percent of the registered TB cases. According to China’s research data in 2013??the PPD positive??≥10 mm??rate of children aged 5 to 15 in different TB epidemic areas was 8.09% to 21.26%. In 2015??6 861 cases of tuberculosis in children were reported nationwide??with a incidence of 3.03/100 000. In 2014??the national TB mortality rate among children aged 0 to 14 was 0.12/100 000. The diagnosis of childhood tuberculosis should be based on a comprehensive assessment of evidence such as contact history??clinical examination and related examinations. The principles of childhood TB treatment are the same as those of adults. At present the state council issued a national tuberculosis control program??put forward to improve the prevention and treatment of tuberculosis in children??to provide technical training to pediatricians on TB control??and to standardize the diagnosis and treatment of childhood tuberculosis.     

Tuberculosis and human immunodeficiency virus co-infection in children: management challenges

The pattern of childhood human immunodeficiency virus (HIV) and tuberculosis (TB) infection mirror these epidemics in the adult population. The number of children co-infected with HIV and TB is rising, and the incidence of congenital and neonatal TB is similarly increasing. In addition, the emergence of multidrug resistant TB and extensively drug-resistant TB has occurred within the context of a high prevalence of HIV and TB. The diagnosis of TB has always been difficult in children and is compounded by HIV co-infection. The clinical symptoms in both diseases are similar, and the radiological changes may be non-specific. Treatment of both conditions in children is a challenge due to drug interactions and problems with adherence. In most developing countries, there are few medicines specifically tested and manufactured for children, with few stable syrup formulations. Thus antituberculosis and antiretroviral tablets have to be divided, giving rise to unpredictable dosing and the possible emergence of resistance. To reduce the morbidity and mortality of TB and HIV, existing childhood TB programmes must be strengthened, and antiretroviral drug therapy and mother-to-child transmission programmes scaled up. An increased emphasis on childhood TB, with early diagnosis and treatment, must be a priority. The provision of isoniazid prophylaxis to HIV-infected children exposed to an adult case of TB or, in areas with a high prevalence of TB, to HIV-infected children (irrespective of a TB contact) may be effective in reducing the morbidity and mortality from childhood TB.     

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.     

Serodiagnosis of childhood tuberculosis by ELISA

Objective: Diagnosis of childhood tuberculosis remains an enigma despite many recent technological developments. The present study has been taken up with the aim to assess the diagnostic potential of mycobacterium tuberculosis excretory-secretory ES-31 antigen and affinity purified anti ES-31 antibodies in the serodiagnosis of different spectrum of childhood tuberculosis.Methods: Mycobacterium tuberculosis H₃₇ Ra excretory-secretory antigen (ES-31) and affinity purified goat anti ES-31 antibodies were used in stick penicillinase ELISA for IgG antibody detection and stick Sandwich penicillinase ELISA for detection of circulating free and immune complexed antigen in the sera of 230 children.Results: Analysis of tubercular antibody, circulating free and immune complexed antigen (CIC-Ag) was done in both pulmonary and extrapulmonary form of childhood tuberculosis and overall sensitivity of 81.4% with a specificity of 93% was achieved for detection of antitubercular IgG antibodies. Of the five cases of pulmonary tuberculosis showing absence of IgG antibody, 3 showed the presence of CIC-Ag and one was found positive for both free and CIC-Ag. Similarly out of 8 cases of extrapulmonary childhood tuberculosis missed by IgG detection 5 were found to be positive for CIC-Ag and 1 showed the positive reaction for both free and immune complexed antigens.Conclusion: IgG antibody to excretory-secretory antigen ES-31 is found to be having good specificity with acceptable sensitivity in detecting different forms of childhood tuberculosis. Further detection of circulating free and / or immunecomplexed antigen can be used as an adjunct tool in the diagnosis of childhood tuberculosis.     

Tuberculosis — persistent threat to human health

With the increasing incidence of tuberculosis worldwide, childhood cases now constitute 40% of the total. TB control thus has global importance. Unfortunately, control of disease is not in sight. It was always thought that adult tuberculosis is the fountainhead of childhood tuberculosis but it is being increasingly realized that it is the infection acquired during childhood that promotes reactivation of adult disease, which in turn maintains the chain of transmission.Thus childhood tuberculosis needs equal or more attention for effective control. Early detection by simple tests and ensuring treatment compliance is the goal. The small number of bacilli and inaccessible sites for bacteriological confirmation makes diagnosis of childhood tuberculosis difficult. Circumstantial evidence is often the basis of diagnosis. However, as clinical manifestations depend upon host immune response and virulence of tubercle bacilli, there is no typical clinical presentation. A large number of infected children may remain asymptomatic, undiagnosed and untreated. Conventional tests such as tuberculin test and radiology are not fully dependable and newer tests have limitations. Poor patient treatment compliance contributes to failure of a tuberculosis control program and leads to drug resistance. To combat this, direct observed treatment (DOTS) has been unanimously recommended in treatment of tuberculosis. DOTS is however estimated to be used in less than 40% of new cases. Misconceptions threaten to undermine continued success in tuberculosis control. TB control is essentially a management problem. Greater accountability of governments, donors and providers is essential     

Increasing rate of childhood tuberculosis in a region of east Croatia

Background: The incidence of childhood tuberculosis as well as the number of children being in contact with persons having tuberculosis has increased in the region of Slavonski Brod during the past decade (1993-2003). The region is located in east Croatia along the border with Bosnia and close to the besieged and destroyed town of Vukovar. The region was heavily involved in recent military activities and migrations in Croatia and Bosnia (1991-1995). Before the war, the population was reasonably well situated, educated and provided with health services. Methods: Routine clinical and epidemiological methods for the diagnosis of tuberculosis were used. Results: A total of 225 cases of tuberculosis were discovered among 271 suspected cases in a total number of 19 623 children below 18 years of age admitted during the last decade to the county hospital (1.38%). The number increased from three patients with tuberculosis in 1993 to 59 in 2003. Discharge diagnoses were: latent infection 40.1%, specific hilar lymphadenopathy 22.1%, primary lung tuberculosis 18.0%, postprimary tuberculosis 3.0%, and contact with infected person but otherwise normal findings 16.9%. The infection was usualy (53.1%) acquired within the family, more often so in younger patients. Bacteriological cultures were positive in 19 of 117 patients with tuberculosis (16.4%). Antituberculosis drug treatment was carried out to completion in all children. Resistance was not encountered. Conclusion: The authors attribute high incidence of childhood tuberculosis in the region of Slavonski Brod, the second highest incidence in Croatia, to the sequellae of migrations during military activities in Croatia and Bosnia (1991-1995) and to the post-war recession.     

Gruźlica i latentne zakażenie prątkami gruźlicy u dzieci. Zastosowanie testów uwalniania interferonu-γ w identyfikacji latentnego zakażenia prątkami gruźlicy u dzieci

The interferon-γ release assays (IGRAs) were developed for the diagnosis of latent tuberculosis infection. IGRAs are currently used for the diagnosis of latent tuberculosis infection in adults; a lack of evaluated studies in children has led to difficulties in their clinical interpretation. These two blood assays, including the commercially available T-SPOT.TB and QuantiFERON, enable detection of circulating T-cells responsive to specific Mycobacterium tuberculosis antigens. These assays are available for use in Poland. Evaluation of these tests has been hampered by the lack of a gold standard for latent tuberculosis infection (LTBI) and limited pediatric data on their use. They may add sensitivity if used in addition to the tuberculin skin test (TST) in the youngest children. A summary of IGRA and TST, their application to pediatric practice and their benefits and limitations are described in this article.     

Potential effect of NICE tuberculosis guidelines on paediatric tuberculosis screening.

OBJECTIVE: Assays based on interferon gamma (IFNgamma) are an exciting new development for screening for latent tuberculosis infection (LTBI) in adults, but there are limited data on their effectiveness in children. Nevertheless new National Institute for Health and Clinical Excellence (NICE) guidelines recommend their use when screening paediatric tuberculosis (TB) contacts. We evaluated the potential effect of the new NICE guidelines on current paediatric practice. DESIGN: Children screened for TB who had had an IFNgamma assay performed (QuantiFERON-TB Gold (QFG)) were included. Actual outcomes from existing guidelines were compared with those that would have been obtained using NICE guidelines. RESULTS: QFG assays were performed on 120 children, 103 as part of TB contact tracing. Six of the 120 (5%) were QFG positive, and seven of the 120 (6%) were indeterminate. Where both Mantoux and QFG results were available, these agreed in 62/104 (60%) of cases. QFG tests were more likely to correlate with a negative Mantoux (98% agreement) than with a positive Mantoux (11% agreement). Management outcomes differed for 23/103 children seen as part of TB contact tracing. Only one (1%) of these had an indeterminate QFG result. 17 (85%) fewer children would have been given LTBI treatment (chemoprophylaxis) and two (2%) children with possible TB would not have been identified using NICE guidelines. CONCLUSION: New NICE guidelines for the use of IFNgamma-based tests for TB screening will reduce the number of children treated for presumed LTBI. Long-term prospective studies are needed to determine the number of children with positive Mantoux tests but negative IFNgamma results who are not given LTBI treatment yet later develop TB.     

Consensus document on treatment of tuberculosis exposure and latent tuberculosis infection in children

INTRODUCTION: The most important causes of the current tuberculosis pandemic are poverty, HIV infection, drug resistance, and the spread of infection by patients with latent tuberculosis infection. In industrialized countries, the main reasons for the increase of this disease are immigration from developing countries and the lack of effective surveillance programs. The situation of children is even more serious as they are more vulnerable to the disease than adults. The children most at risk are those who live with adults at risk for tuberculosis, immigrant children, and adoptees from developing countries. Although children are bacilliferous only exceptionally, the appropriate management of bacilliferous tuberculosis exposure and latent tuberculosis infection in children contributes to the creation of close surveillance of nuclear families and rigorous study of contacts. Moreover, it could prevent serious forms of the disease, which are more frequent in children. OBJECTIVE: The principal objective of this second consensus document of the Spanish Society of Pediatric Infectious Diseases (Sociedad Espa?ola de Infectología Pediátrica [SEIP]) is to unify the criteria for the treatment of tuberculosis exposure and latent tuberculosis infection in children. A further aim is to increase awareness of the need for strict detection measures in high-risk populations among health authorities.     

Pediatric tuberculosis pyramid and its fate with and without chemotherapy/chemoprophylaxis

The latest available information on total and infectious cases of tuberculosis in the country and also large number of sputum positive cases being detected annually, particularly after the involvement of multipurpose workers in the primary health care programme for the control of tuberculosis, is presented. The consequences of the large pool of infectious cases in the population lead to spread of bacilli to children with development of primary infection in them. These children with primary infection, specially high risk group in infancy and early childhood, get serious complications of the disease. It may be emphasized that BCG vaccination cannot prevent the lodgement of tubercle bacilli in the lung but can only contain or restrict haematogenous spread. Inspite of increasing coverage of infants with BCG vaccination there are an increasing number of cases of intrathoracic tuberculosis, particularly various groups of mediastinal nodes. However, to a lesser extent haematogenous complications do occur in malnourished children, as BCG has a limited value in preventing serious complications in children with malnutrition. The clinical pattern of pediatric tuberculosis has also changed in vaccinated and partly or inadequately drug treated children. Hence, chemoprophylasis/ chemotherapy to prevent complications of primary infection has been tried. Even relatively privileged children in developed countries are reported to have complications of primary infection to an extent of 10 to 15%, as per the studies all over world. So preventive chemoprophylaxls, preferably with two bactericidal drugs, should be considered as the main strategy for controlling primary infection. Chemoprophylaxis with two drugs should be used as incidence of isoniazid resistant bacilli has increased. All concerned with child health should consider the strategy of treatment of primary infection in high risk children by chemoprophylaxis by starting a large multicentric trial both in urban and rural areas, as a part and parcel of primary health care intervention already in practice for cases of sputum positive pulmonary tuberculosis.     

Preventing tuberculosis in childhood

Almost half of the cases of tuberculosis requiring treatment may arise in children. The strategies to control tuberculosis in developing countries remain firmly focussed upon adults who are smear positive. The prevention of tuberculosis in childhood has two aspects: prevention of infection and management of infection once it has occurred. The steps for prevention of infection include early diagnosis of adults with tuberculosis who are culture positive but not yet smear positive. Use of ultraviolet lighting or atleast large windows and ventilation in the area where patients are kept may reduce the infection rate. An appropriate regimen and supervised chemoprophylaxis to ensure good compliance may be an important step towards control of tuberculosis infection. Above all we must try by every means to prevent tuberculosis in infants and small children and give the best possible opportunities for recovery to those already freshly infected.