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Fatma TRITAR Dept of Respiratory Diseases C Tuberculosis Multidrug Resistance Unit Abderrahmen Mami Hospital, Ariana, Tunisia The First annuel conference of LATA 24 March 2016- Beyrouth Chilhood Tuberculosis (TB) Childhood TB is an indication of failing TB control in the community. It allows disease persistence in the population. Mortality and morbidity due to TB is high in children. HIV co-infection and MDR diseases are as frequent in children as in adults. In most settings, children with TB continue to be given low priority by national TB control programmes (NTP) because they are less likely to transmit disease Epidemiology Childhood TB accounted for 3.5% of the global TB caseload in high-burden countries In 2013, WHO estimate that there a total of : 550000 childhood tuberculosis cases 80000 deaths in children due to TB An estimate that only included human immunodeficiency virus (HIV)-uninfected children There are no data of the numbers of TB-related deaths in HIVinfected children, the greatly increased risks of TB and of TBrelated mortality • Graham SM,. Importance of tuberculosis control to address child survival. Lancet 2014 • World Health Organization. Global tuberculosis report 2014. Geneva, Switzerland: WHO, 2014. • Dodd PJ. Burden of childhood tuberculosis in 22 high-burden countries. Lancet Global Health 2014 Epidemiology TB disease and latent TB infection (LTBI) frequencies are dramatically underestimated : 1. Paucibacillary disease in infants and children 2. Difficulty of confirming the diagnosis of TB Epidemiology > 90% of TB disease progression in young children occurred within 12 months of primary M. tuberculosis infection Most TB cases occur in children under five year Extra-pulmonary TB (mediastinal lymphadenopathy) and severe and disseminated TB (TB meningitis and miliary) occurs mostly in young children (< 3 years) HIV co-infection An estimated 2.5 million children <15 years were infected with HIV • Majority living in sub-Saharan Africa • HIV prevalence in countries with moderate-to-high prevalence = 10% to 60%. • In the absence of ART, more than 20% of HIV-infected children living in high-burden areas would develop TB disease, leading to a three- to six-fold higher mortality Drug-resistant TB • Among children living with drug-resistant patients, an overall high prevalence of TB was observed : 7.5% • In Thailand, 5.7% of specimens from children were MDR-TB in 2012 revealing a drastic increase in a few years • Recent Indian survey, half of the children with drug sensitivity tests (DSTs) harboured drug-resistant strains, of which 50% were MDR-TB. 1. Amanullah F. High tuberculosis prevalence in children exposed at home to drugresistant tuberculosis. Int J Tuberc Lung Dis 2014 2. Lapphra K. Drug-resistant tuberculosis in children in Thailand. Int J Tuberc Lung Dis 2013 3. Jain SK, Ordonez A, Kinikar A, et al. Pediatric tuberculosis in young children in India: a prospective study. Biomed Res Int 2013 Management of childhood TB Why Difficult ? Difficulty of establishing a definitive diagnosis : 1. TB pauci-bacillary 2. Excavations formation is relatively rare (6% ) in children aged under 13 years 3. Challenges of obtaining respiratory samples 4. Presence of extra-pulmonary disease 5. Wide spectrum of disease manifestations and severity that often overlap with other common childhood conditions (pneumonia, HIV associated lung disease, malnutrition) Lower priority to public health In current practice …. • The mother of two children (2 and 4 years) • Very worried, consult because their grand mother is treated for one week for pulmonary TB • They are vaccinated with BCG • They sleep with their grandparents once a week, in the same room as their grandmother. Question : What are we doing ? 1. Search and treat TB disease 2. Manage latent infection TB Diagnosis of TB in children • Symptoms of childhood TB are nonspecific, and up to 50% of children may be asymptomatic in the early stage • The diagnosis of tuberculosis in children is challenging, especially in infants and young children (<5 years), who are at particular risk for disease and adverse outcomes from tuberculosis 1. Zar HJ. Diagnosis of pulmonary tuberculosis in children. Exp Rev Anti-infect Therapy 2010 2. Oliwa JN KJ. Tuberculosis and childhood pneumonia in tuberculosis endemic settings-common, cause or consequence? A review of the evidence. Lancet Resp Med 2015. Diagnosis of TB in children • It is important to always take into account: Age Nutritional status • Risk factors for TB infection: History of contact with a TB patient Generally, children develop TB within 2 years of exposure or even a year in most cases (90%) Evolution of risk factors to active TB disease: young, HIV infection, malnutrition, recent measles Clinical Examination • BCG scar • Break of the growth curve • Peripheral lymphadenopathy Tuberculous lymphadenopathy • Most common form of EPT in children • 10% of cases of childhood TB. • The age of onset is usually between 2 and 10 years • The most commonly affected are the cervical nodes • TB lymph node may be associated with other symptoms of TB. • Spontaneous perforation (fistula) and a flow may occur. Chest radiography 70% of infected children < 5 years Chest RX is abnormal : • • • • Mediastino-pulmonary opacity Condensations systematized, nodules Alveolar opacities Isolated lymphadenopathy Boloursaz MR. Acta Med Iran. 2010 ;48:244-9. Severe forms Mediastinal lymphadenopathy rights in a child ventilation disorder top right in an infant ventilation disorder left lung in an infant Pericardial tuberculosis effusion Computed tomography (CT) • More sensitive than chest radiography (< 4 years) • Adenopathies or a pathological infiltrate in 60-85% of children with normal chest radiography . Nodules, infiltrating Condensations Delacourt C. Rev Mal Respir 2011; 28: 529–541 Garrido JB. PediatrPulmonol. 2012 ;47:895-902. Computed tomography (CT) • In infants, chest CT scans revealed extensive parenchymal lesions and hilar/mediastinal lymph node enlargement • Airway complications are frequently missed by chest RX • CT scan sensitivity for prediction of severe bronchial involvement = 100% (specificity 72%) Lymphadenopathy with tracheobronchial Complications Arlaud K. Arch Dis Child 2010; 95: 125-129. Extensive TB Multivisceral disease Lymph node cervical, Mediastinal, abdominal Lung and hepatic TB Miliary tuberculous Bacteriological confirmation • Younger children rarely produce good quality respiratory specimens, and TB is associated with a low bacillary burden in children. • The diagnosis of childhood TB is mostly presumptive. • TB suspicion should be confirmed whenever possible, using new available tools, particularly in case of pulmonary and lymph node TB. 1. Zar HJ. Diagnosis of pulmonary tuberculosis in children: new advances. Exp Rev Anti-infect Therapy 2010 2. Nicol MP. New specimens and laboratory diagnostics forchildhood pulmonary TB: progress and prospects. Paediatr Resp Rev 2011 3. World Health Organization. Policy update: Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Available at: December 2014. Bacteriological diagnosis Sample collection: Sputum and GLA Smear microscopy performs poorly in both sputum and GLA Alternative methods of sample collection o Hypertonic saline-induced sputum collection (> 30%) o Nasopharyngeal aspiration (NPA) (easy to perform and more sensitive than GLA) o Endoscopy with broncho-alveolar lavage o lymph node fine-needle aspiration biopsy (FNAB). (60% diagnostic confirmation (histo / Bacteriology) * Multiply the samples to increase rentability GLA+ induced sputum * Check DST of contaminating + Bacteriological diagnosis • Depending on the study setting and resources, microbiological confirmation is established by culture in only 15%-50% of pediatric cases. • Although the recently endorsed Xpert MTB/RIF assay is more sensitive and specific than smear microscopy in children with tuberculosis, it only has a sensitivity of approximately 66% on respiratory specimens compared with culture 1. Zar HJ. Diagnosis of pulmonary tuberculosis in children: new advances. Exp Rev Anti-infect Therapy 2010 2. Nicol MP. New specimens and laboratory diagnostics forchildhood pulmonary TB: progress and prospects. Paediatr Resp Rev 2011 3. World Health Organization. Policy update: Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Available at: December 2014. Molecular biology The Xpert MTB/RIF assay • The most popular molecular diagnosis test • Improve the rentability of bacteriological diagnosis • Using two induced sputum specimens detected twice as many cases (75.9%) compared with sputum smear (38%) • Rapid detection of possible resistance • Confirmation yet recommended conventional DST GeneXpert real-time PCR detection of DNA Tortoli E, EurRespir J. 2012; 40:442-7. Molecular biology The Xpert MTB/RIF assay • Pulmonary TB : Sensitivity (sputum and GLA) 96% in smear-positive children 55% in smear-negative children Specificity = 98% • Extra-pulmonary TB : Sensitivity = 87% pleural fluid (100%) peripheral lymph nodes (86%) CSF (75%) Specificity = 81%-99% WHO recommendations Xpert MTB/RIF should be used rather than conventional microscopy and culture as the initial diagnostic test in children suspected of having multidrug-resistant (MDR)-TB or HIV-associated TB, or in cases of TB meningitis testing CSF Bronchoscopy • Bronchoscopy showed airway anomalies in half of the children with lymphadenopathy on chest radiography. • Early detection and effective treatment of endobronchial TB is essential in order to decrease secondary bronchial stenosis and bronchiectasis Bronchi complications Chun-Mei Hu, J Thor Dis 2013, 5(4) S Eren, Turkish thoracic journal 2009. Bronchoscopy Evaluation of tracheobronchial lesions LBA: bacteriology Transbronchial needle aspiration (TBNA) Endoscopic treatment caseum Inflammation Compression of the bronchus adenomegaly fistulized Chun-Mei Hu, J Thor Dis 2013, 5(4) Arlaud K. Arch Dis Child. 2010 ;95:125-9. Bronchoscopy • Mediastinal lymph nodes may be sampled safely using transbronchial needle aspiration (TBNA) through flexible bronchoscopy . • A prospective study in 28 children with large subcarinal lymphadenopathy reported that TBNA provided a definitive diagnosis of mycobacterial infection in 50% of patients. Goussard P. The diagnostic value and safety of transbronchial needle aspiration biopsy in children with mediastinal lymphadenopathy. Pediatr Pulmonol 2010. Immunoassays : Control of exposure and infection ! Tuberculin skin test (TST) TST positive is useful to indicate TB infection when there is no known exposure to TB clinical evaluation (no contact history) Useful to enhance the diagnosis of TB in children with clinical features are suggestive of TB but whose sputum smear is negative or who can not produce sputum Level of positivity? in any child, regardless of BCG immunization : TST ≥ 10 mm in children severely malnourished : TST ≥ 5 mm TST positive does not distinguish TB infection to active TB disease TST negative does not rule out active TB disease Immunoassays? Control of exposure and infection! Test for production of gamma interferon: IGRA Quantiferon, Spot TB test : • In both active and presumed latently infected young children, the immune system is immature, and is the likely cause of lower cytokine release and compromised IGRA performance • Poor sensitivity before the age of 5 years There is no evidence to support the use of IGRA over TST in young children under five Therefore, IGRAs should not replace the TST in TB diagnosis in this age group. Nevertheless, they could add sensitivity to the results of the TST testing. Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update Stephen M. Graham Clinical Infectious Diseases 2015 Evaluation of data from active case-finding studies have reported that 12% and 65% of children with confirmed tuberculosis did not have clinical features consistent with the standardized “clinical signs/symptoms suggestive of tuberculosis” used to categorize clinical, unconfirmed cases. 1. Beneri C. Understanding NIH clinical case definitions for pediatric intrathoracic TB by applying them to a clinical trial. Int J Tuberc Lung Dis 2015. 1. WisemanCA.NovelapplicationofNIH case definitions in a paediatric tuberculosis contact investigation study. Int J Tuberc Lung Dis 2015 Intrathoracic tuberculosis diagnostic criteria 1. Microbiological confirmation Addition of WHO-endorsed NAAT (eg, Xpert/RIF MTBassay) 2. Clinical signs/symptoms suggestive of tuberculosis Well-defined symptoms/signs that are highly suggestive of TB 3. Interpretation of chest radiographs 4. Tuberculosis exposure Time-window reduced to “within the past 12 months.” 5. Mycobacterium tuberculosis infection TST and/or IGRA positive; methods and cutoffs used must be specified 6. Response to treatment 2010 Treatment of Chilhood Tuberculosis (TB) Children require higher drugs dosages than adults . Short courses of steroids are associated with TB treatment in case of respiratory distress Fibroscopic desobstruction is proposed for severe airways involvement Antiretroviral therapy is mandatory in case of HIV infection. Treatment of Chilhood Tuberculosis (TB) Combined Forms : HRZ 30/60/150 mg HR 30/60 mg Treatment of Chilhood Tuberculosis (TB) Children with suspected or confirmed pulmonary TB or tuberculous peripheral lymphadenitis who live in settings with low HIV prevalence or low resistance to isoniazid Children who are HIV-negative can be treated with : o Three-drug regimen (HRZ) for 2 months o Followed by two-drug (HR) regimen for 4 months o Total duration of treatment being 6 months Treatment of Chilhood Tuberculosis (TB) • Children living in settings where the prevalence of HIV or resistance to isoniazid is high • Children with extensive pulmonary disease • Should be treated with : o Four-drug regimen (HRZE) for 2 months o Two-drug regimen (HR) for 4 months o Total duration of treatment being 6 months Treatment of Chilhood Tuberculosis (TB) Addition of a fourth drug such as ethambutol is necessary in complicated pulmonary TB or meningeal involvement or oste-oarticular tuberculosis : o Four-drug o Followed o Total regimen (HRZE) for 2 months by a two-drug regimen (HR) for 10 months duration of treatment being 12 months . For infants < 6 months of age with widespread dissemination, ethionamide use was reported in place of ethambutol considering its superior penetration into the central nervous system*. * American Academy of Pediatrics Stop TB partnership childhood TB subgroup. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Int J Tuberc Lung Dis 2006 Additional medications • Steroid therapy is usually indicated in cases of severe bronchial obstruction, meningeal involvment, pericard. • Prednisone (1-2 mg/kg/day - maximum 60 mg/day) for 4 weeks followed by reduction dose for 2 weeks • Combining 4 weeks of steroids and possibly endoscopic resection demonstrated good results and dramatically reduced the need for surgery. • In severe pulmonary TB, additional antibiotics may be required for bacterial co-infections. Management of LTBI • Post-exposure prophylaxis in children is a highly effective strategy to reduce the risk of TB disease. • IPT is recommended for any HIV-positive child with TB exposure, irrespective of the child’s age or TST result, once active TB has been excluded Treatment options for LTBI The following treatment options are recommended for the treatment of LTBI: • 6-month isoniazid, • 9-month isoniazid, • 3-month of weekly rifapentine plus isoniazid, • • 3-4 months isoniazid plus rifampicin, 3-4 months rifampicin alone (Strong recommendation, moderate to high quality of evidence) Treatment options for LTBI Management of LTBI A short-course regimen with isoniazid and rifampicin for 3 months could be better then 9 month course of isoniazid monotherapy regarding compliance and chest radiography evolution, and showed a significant decrease in childhood TB that persisted to 12 years of follow-up Preventive treatment for contacts of MDR-TB cases ? The optimal therapy for treatment of latent infection with a presumably multidrug-resistant Mycobacterium tuberculosis strain is currently not known • • MDR-TB prophylaxis is much more controversial. We need urgent valuation of appropriate chemo- prophylactic regimens for child contacts of patients with MDR-TB Van der Werf MJ .Lack of evidence to support policy development for management of contacts of multidrug-resistant tuberculosis patients : two systematic reviews. Int J Tuberc Lung Dis 2012 Prevention BCG • BCG remains the only available vaccine for TB worldwide • The global BCG efficacy is estimated to be 50% • BCG vaccination at birth halved neonatal mortality from non-TB infections Childhood tuberculosis • Childhood tuberculosis (TB) is a preventable and curable infectious disease • Remains overlooked by public health authorities, health policy makers and TB control programmes. • Despite being a major contributor to childhood morbidity and mortality particularly in high TB-burden settings and advocacy and scientific progress are still insufficient. • Childhood TB contributes significantly to the burden of disease and represents the failure to control transmission in the community. The pool of infected children constitutes a reservoir of infection for the future burden of TB. Childhood tuberculosis • Guidelines for childhood TB management have been developed and are already adopted by many countries • It is time to prioritise childhood TB, advocate for addressing the challenges and grasp the opportunities in its prevention and control. Thank you