244 www.thelancet.com/respiratory Vol 3 March 2015 Review Lancet Respir Med 2015; 3: 244–256 See Comment page 179 Centro de Investigação em Saude de Manhiça, Maputo, Mozambique (E López-Varela MD, A L García-Basteiro MD); ISGlobal, Barcelona Centre for International Health Research, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain (E López-Varela, A L García-Basteiro); Unidad Enfermedades Infecciosas Pediátricas, Departamento de Pediatría, Hospital General Univesitario Gregorio Marañón, Madrid, Spain (B Santiago MD); Laboratorio Inmunobiología Molecular, Hospital General Univesitario Gregorio Marañón, Madrid, Spain (B Santiago); Center of Infectious Diseases and Travel Non-tuberculous mycobacteria in children: muddying the waters of tuberculosis diagnosis Elisa López-Varela, Alberto L García-Basteiro, Begoña Santiago, Dirk Wagner, Jakko van Ingen, Beate Kampmann Non-tuberculous mycobacteria (NTM) are a large family of acid-fast bacteria, widespread in the environment. In children, NTM cause lymphadenitis, skin and soft tissue infections, and occasionally also lung disease and disseminated infections. These manifestations can be indistinguishable from tuberculosis on the basis of clinical and radiological indings and tuberculin skin testing. A diagnostic and therapeutic problem for respiratory physicians and other clinicians is therefore evident, particularly in settings where childhood tuberculosis is common, and bacteriological conirmation of any mycobacterial disease is diicult because of low availability of laboratory services in low-resource settings and the inherent paucibacillary nature of mycobacterial disease in childhood. The epidemiology of NTM varies by world region, and attempts to understand the burden of NTM disease and to identify risk factors in the paediatric population are hampered by inadequate mandatory NTM reporting and the overlap of clinical presentation with tuberculosis. The immune response to both NTM and Mycobacterium tuberculosis is based on cellular immunity and relies on the type-1 cytokine pathway. The disruption of this immune response by genetic or acquired mechanisms, such as mendelian susceptibility to mycobacterial disease or HIV, might result in predisposition to mycobacterial infections. Published diagnostic and management guidelines do not provide speciic advice for diagnosis of NTM in children, from whom the quantity and quality of diagnostic samples are often suboptimum. Treatment of NTM infections is very diferent from the treatment of tuberculosis, depends on the strain and anatomical site of infection, and often involves antibiotic combinations, surgery, or both. In this Review, we summarise the epidemiological and clinical features of NTM infection in children, with a speciic focus on the implications for public health in settings with a high endemic burden of childhood tuberculosis. Introduction The Mycobacterium genus is divided into three groups: the Mycobacterium tuberculosis complex, Mycobacterium leprae, and the remainder, collectively labelled non-tuberculous mycobacteria (NTM). NTM are a large family of microorganisms common in soil and water. Most of them are non-pathogenic, but some can cause human disease. 1,2 NTM and Mycobacterium tuberculosis complex share microbiological attributes, induce similar immune responses, and have overlapping clinical manifestations, particularly diseases of the lymph node and lung. However, disease caused by NTB is a diagnostic challenge for respiratory physicians, paediatricians, and other clinicians because it cannot readily be distinguished from tuberculosis on the basis of clinical history, tuberculin skin test results, radiological patterns, 3 and initial laboratory reports. In children, NTM infection can result in cervical lymphadenitis, skin and osteoarticular infections, lung disease (although rare in the absence of chronic lung disorders), and disseminated infections in the setting of primary or acquired immune deiciencies. 1,4–6 Diagnosis is especially challenging in children living in regions where tuberculosis is highly endemic and where epidemiological and clinical studies of NTM diseases are scarce. 7–10 The underlying diagnosis is most often assumed to be childhood tuberculosis, and standard tuberculosis treated is started empirically. However, the treatment of NTM is very diferent from that of tuberculosis, making the initial correct diagnosis essential to ensure appropriate treatment. When paediatric respiratory samples are available, diagnosis of tuberculosis in most high-burden settings is initially based on smear microscopy, which is often negative in children due to the paucibacillary nature of tuberculosis in children. If present in a smear, M tuberculosis and NTM cannot be distinguished Key messages • Non-tuberculous mycobacteria (NTM) are environmental organisms that can cause disease in adults and children • NTM and tuberculosis disease are often clinically indistinguishable • In settings with a high burden of tuberculosis, little data for the epidemiology and clinical burden of NTM disease are available, the ability to conirm mycobacterial disease microbiologically is poor, and NTM-speciic treatment options are not widely available • Data for the epidemiology of NTM in children, including transmission mechanisms and risk factors, are scarce • NTM exposure seems to afect the eicacy of Bacillus Calmette–Guérin vaccination, although the mechanism is unclear • The most common NTM-associated disease in children is NTM lymphadenitis; other clinical manifestations include skin and soft tissue infections, lung disease (predominantly in people with previous lung comorbidities), and disseminated infections (mostly in immune-compromised children) • Diagnosis of both tuberculosis and NTM disease should be based on clinical, radiological, and microbiological assessment; diagnostic criteria for NTM pulmonary disease speciically for children do not exist • NTM isolation from non-sterile sites, such as gastric aspirate and sputum, does not necessarily imply disease • The treatment strategy for NTM disease depends on the species, site, disease severity, and, in most tuberculosis-endemic countries, on the availability of drugs and trained surgical personnel • NTM frequently develop resistance to antimicrobial drugs; thus, medical management relies on antibiotic combinations, with macrolides as the cornerstone of treatment • Studies of the clinical and programmatic efect of new diagnostic algorithms for NTM based on the Xpert MTB/RIF assay are needed JG 14TLRM0538_LÓpez-Varela THELANCETRM-D-14-00538R1 S2213-2600(15)70007-X Embargo: [add date when known]