Pediatr Radiol (2017) 47:1260–1268 DOI 10.1007/s00247-017-3866-1
MINISYMPOSIUM: IMAGING OF CHILDHOOD TUBERCULOSIS
Imaging of thoracic tuberculosis in children: current and future directions Kushaljit Singh Sodhi 1 & Ashu S. Bhalla 2 & Nasreen Mahomed 3 & Bernard F. Laya 4
Received: 30 December 2016 / Revised: 11 March 2017 / Accepted: 9 April 2017 / Published online: 26 August 2017 # Springer-Verlag Berlin Heidelberg 2017
Abstract Tuberculosis continues to be an important cause of morbidity and mortality worldwide. It is the leading cause of infection-related deaths worldwide. Children are amongst the high-risk groups for developing tuberculosis and often pose a challenge to the clinicians in making a definitive diagnosis. The newly released global tuberculosis report from World Health Organization reveals a 50% increase in fatality from tuberculosis in children. Significantly, diagnostic and treatment algorithms of tuberculosis for children differ from those of adults. Bacteriologic confirmation of the disease is often difficult in children; hence radiologists have an important role to play in early diagnosis of this disease. Despite advancing technology, the key diagnostic imaging modalities for primary care and emergency services, especially in rural and low-resource areas, are chest radiography and ultrasonography. In this article, we discuss various
* Kushaljit Singh Sodhi
[email protected]
1
Department of Radiodiagnosis & Imaging, Post Graduate Institute of Medical Education & Research (PGIMER), Sector-12, Chandigarh 160012, India
2
Department of Radiodiagnosis, All India Institute of Medical Sciences (AIIMS), New Delhi, India
3
Department of Radiology, Rahima Moosa Mother and Child Hospital, University of Witwatersrand, Johannesburg, South Africa
4
Institute of Radiology, St. Luke’s Medical Center-Global City, Taguig City, Philippines
diagnostic imaging modalities used in diagnosis and treatment of tuberculosis and their indications. We highlight the use of US as point-of-care service along with mediastinal US and rapid MRI protocols, especially in mediastinal lymphadenopathy and thoracic complications. MRI is the ideal modality in high-resource areas when adequate infrastructure is available. Because the prevalence of tuberculosis is highest in lower-resource countries, we also discuss global initiatives in low-resource settings. Keywords Chest . Children . Diagnosis . Imaging . Tuberculosis
Introduction Tuberculosis ranks among the top 10 causes of death worldwide, as per the recently released 2016 World Health Organization global report on tuberculosis [1]. Although number of deaths and the incidence rate of tuberculosis continues to fall, still in 2015 there were an estimated 10.4 million new (incident) cases of tuberculosis worldwide, of which 1.0 million (10%) were children [1]. The World Health Organization also estimates that two-thirds of the world’s population has no access to basic radiology services and that when available, the quality and safety of the procedures are sometimes questionable or even dangerous to the patient, the health care worker and the public. Such conditions are most prominent in lowresource countries with insufficient infrastructure, an unstable political environment and a considerable burden of the disease. In such areas, diagnostic imaging services are rarely seen as a global health priority and are not integrated into national health plans [2–5]. In this review we discuss various diagnostic imaging modalities used in the evaluation of primarily
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intrathoracic tuberculosis and their indications. We also cover global initiatives in low-resource settings.
World Health Organization global strategy The milestone set as part of the World Health Organization (WHO) “End Tuberculosis Strategy” is a 35% reduction in the absolute number of deaths from tuberculosis and a 20% reduction in the incidence of tuberculosis, compared with levels in the year 2015, by 2020 [1]. The proportion of patients who die from tuberculosis, referred to as the case fatality ratio, in 2015 varied from less than 5% in a few countries to more than 20% in many countries in the African region. This shows extensive inequalities among countries in access to timely diagnosis and treatment, which the WHO is working to address. If every patient with tuberculosis had a timely diagnosis and high-quality treatment, the fatality ratio for tuberculosis would be low in all countries [1]. In clinical practice, early diagnosis of pulmonary tuberculosis in children is often difficult and challenging because of the nonspecific clinical signs and the limitations of the tuberculin skin test [6–9]. These limitations include the need for a follow-up visit to interpret the results, different interpretation criteria in different clinical settings, possibility of false-positive results with Bacillus Calmette-Guerin (BCG) vaccination or other environmental mycobacteria. The effect of the BCG vaccination on the tuberculin skin test is extremely modest after 10 years or more if the vaccination is administered in infancy [8]. Because of these limitations of the tuberculin skin test, interferon-gamma release assay has been used in latent tuberculous infection [10]. Interferon-gamma release assay measures interferon gamma released in response to T-cell stimulation by specific Mycobacterium tuberculosis antigens. This test has been shown to be more specific than the tuberculin skin test because it is not affected by the BCG vaccination. Two interferon-gamma release assays are approved by the United States Food & Drug A d m i n i s t r at i o n : T- S P O T. T B Te s t ( T- S p o t ) a n d QuantiFERON-TB Gold In-Tube Test (QFT-GIT). However, these are being used in high-resource countries and their use in high-burden areas and low-resource settings remains a challenge. The World Health Organization has published recommendations against their use in lowand medium-income countries [11]. A few systemic reviews and meta-analyses performed to assess the value of interferon-gamma release assay and the tuberculin skin test in the diagnosis of tuberculosis infection in children have reported similar accuracies [12].
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Limitations of the microbiological diagnosis of tuberculosis in children Sputum smear microscopic examination for acid-fast bacilli is reported to be a rapid, universally affordable tool for diagnosis of pulmonary tuberculosis but is limited by low and varied sensitivity rates [13, 14]. This is especially true in children because of the paucibacillary nature of childhood tuberculosis. Sputum smear microscopy from induced sputa and gastric washings has a reported yield of only 4–7% [15, 16]. Tuberculosis culture has yields of 30–40% but takes much longer to process [7]. In the last decade, molecular and non-molecular assays have been built up for early detection of active tuberculosis. So far the only World Health Organization-recommended rapid diagnostic test for detection of tuberculosis currently available is the Xpert mycobacterium tuberculosis/rifampicin assay for rapid concurrent diagnosis of disease and drug resistance; however it has not been universally adopted. Because of these limitations, imaging plays a significant role in the evaluation of children suspected of having thoracic tuberculosis.
Imaging of thoracic tuberculosis The role of imaging in thoracic tuberculosis is threefold: diagnosis, assessment of response, and detection of complications [16]. Thoracic involvement in tuberculosis can be pulmonary, lymph nodal, pleural or a combination of these. Although cardiac, breast, chest wall and vertebral (skeletal) involvement in thoracic tuberculosis is well known, these are beyond the scope of this review. In low-resource and rural areas, the key diagnostic imaging modalities for primary care and emergency services are plain radiographs and US, which together can meet the majority of imaging needs of the population. CT and MRI in these areas are available only in tertiary centers and hence are used as problemsolving modalities. Although various imaging modalities can help in detection of disease and its sequelae and suggest disease activity, definitive diagnosis requires microbiological identification and confirmation of tuberculosis by culture [13, 16].
Imaging modalities Chest radiography Typical radiographic findings are listed in Table 1. Chest radiography is the primary radiologic modality used in the evaluation of any suspected thoracic tuberculosis. Chest radiography is routinely incorporated into various screening and
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Pediatr Radiol (2017) 47:1260–1268 Radiographic findings in pulmonary tuberculosis
Radiographic findings highly suggestive of tuberculosis
Radiographic findings suggestive of tuberculosis but nonspecific
Hilar/paratracheal/sub-carinal lymphadenopathy
Equivocal paratracheal stripe widening/hilar enlargement
Ipsilateral parenchymal lesion with lymphadenopathy
Consolidation
Miliary nodules Cavities with surrounding consolidation/thick walls
Air-space/indeterminate nodules Thin-walled cavities
Pleural effusion with co-existent lymphadenopathy and lung parenchymal disease
diagnostic algorithms. It has been used by clinicians and radiologists for making initial diagnosis as well as for monitoring response to treatment and looking for complications in children with tuberculosis (Fig. 1). However it can be normal in many patients (up to 15%) with proven tuberculosis [17–20]. Also, chest radiography is not specific for tuberculosis and is thus limited by its poor specificity and poor interobserver agreement [19]. According to international standards of tuberculosis care, all patients, including children, with unexplained cough lasting 2 weeks or more or with unexplained findings suggestive
of tuberculosis on chest radiographs should be evaluated for tuberculosis. Thus chest radiograph serves as an entry point for tuberculosis diagnostic evaluation [21]. Accurate diagnosis of pulmonary tuberculosis on chest radiograph is dependent on the reader’s expertise because the technique of chest radiograph interpretation is still not standardized. Furthermore, practice guidelines for standard chest radiography vary among institutions. In some countries a standa rd c he st rad iog rap hy p roto col inclu de s eith er anteroposterior (AP) or postero-anterior (PA), and lateral views; in other countries lateral radiographs are not always
Fig. 1 Typical radiographic findings in thoracic tuberculosis. a Frontal chest radiograph in an 8-year-old boy with positive family history of pulmonary tuberculosis reveals right paratracheal (arrow) and bilateral hilar (arrowheads) lymphadenopathy, one of the classic findings in thoracic tuberculosis. b, c Anteroposterior (b) and lateral (c) chest radiographs in a 17-month-old boy with culture-confirmed pulmonary tuberculosis demonstrate the radiographic hallmark of pulmonary tuberculosis, i.e. bilateral hilar lymphadenopathy (arrowheads in b) with airspace consolidation (asterisk in b); and incomplete doughnut
sign (arrow in c) formed by the normal right and left main pulmonary arteries and the aortic arch anteriorly and superiorly and the hilar and subcarinal lymphadenopathy inferiorly. d Frontal chest radiograph in a 4year-old girl with culture-confirmed pulmonary tuberculosis demonstrates numerous tiny (<3-mm) nodules randomly distributed throughout both lungs, compatible with miliary tuberculosis. e Anteroposterior chest radiograph in an 11-month-old girl with pulmonary tuberculosis demonstrates right upper lobe consolidation/ collapse (asterisk) with bilateral hilar lymphadenopathy (arrowheads)
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performed as a part of standard protocol. The World Health Organization guidelines recommend including lateral radiographs in children. Many studies have been performed to determine the sensitivity and specificity of chest radiography in the diagnosis of tuberculosis [20]. While intrathoracic (mediastinal and hilar) lymphadenopathy is the radiologic hallmark of pulmonary tuberculosis on chest radiographs, an important limitation is the poor interobserver agreement [6, 7, 9, 22, 23]. Interobserver and intra-observer agreement on chest radiographs in the detection of lymphadenopathy in children have been recorded as fair and moderate, which is of concern [22, 23]. Chest radiography has a reported sensitivity of 67% and specificity of 59% in detection of enlarged mediastinal lymph nodes in children. It has been reported that the addition of a lateral view to a postero-anterior view did not significantly increase the sensitivity or specificity of chest radiographs in detection of lymph nodes in children [24]. However Smuts et al. [25] and Andronikou et al. [26] strongly advocate the use of lateral chest radiographs in lymph nodal detection and conclude that its addition improves the accuracy in detection of lymphadenopathy. A chest radiograph reading and recording system was initially proposed as a structured format for chest radiographic evaluation to provide satisfactory intra- and inter-reader agreement in order to make it suitable for epidemiological surveys of tuberculosis and other lung diseases [27]. However this did not get universally incorporated into actual practice. Teleradiology has been successfully integrated in lowresource settings with limited availability of radiologists [23]. Significantly, radiographs are poor indicators of disease activity and CT scan is often performed for differentiating active from latent tuberculous infection or inactive disease [20]. A recent meta-analysis indicates that all scoring systems proposed from 1899 to 2012 used a combination of clinical or laboratory and radiologic data, and that none was based on imaging parameters alone [28]. In a large tuberculosis screening program, chest radiography was shown to have a low yield in the detection of active tuberculosis and it offered no assistance in prioritizing individuals for latent tuberculous infection treatment [29]. The term “inactive tuberculosis” on radiographs is now largely replaced by “radiologically stable disease”. A negative sputum culture and radiographically stable lesion for 6 months are considered the best indicators of inactive disease. However stable lesions can still contain active tubercular bacilli [13]. From a future perspective, computer-aided systems for detecting pulmonary tuberculosis have shown promising preliminary findings [30]. These have accurately distinguished chest radiographs of culture-positive tuberculosis cases in large cohorts and controls. These systems have the potential to change overall diagnostic utility of chest radiographs in tuberculosis; however further studies are required on its cost-effectiveness and operational aspects before advocating its place in various
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diagnostic and screening algorithms [30]. There is also a paucity of literature pertaining to computer-aided detection of pulmonary tuberculosis in children. Ultrasound US imaging offers several advantages, particularly in low-resource areas, for the diagnosis of thoracic tuberculosis in children. It does not involve any radiation, is easily available, affordable, obviates need for sedation and can be performed at the bedside (portable). It is useful in the detection and characterisation of pleural effusion and in guiding aspiration and drainage procedures (Fig. 2). Mediastinal US has been proposed as an alternative to chest radiograph in the detection of mediastinal lymph nodes, specifically in resource-limited settings where US might be the only imaging modality [9, 31]. A study investigating children with pulmonary tuberculosis who had normal chest radiographs found mediastinal lymphadenopathy in 67% of children using US of the mediastinum [9, 32, 33]. On US, lymph nodes are well-defined hypoechoic structures, oval in shape, and can be easily identified as distinct from adjacent mediastinal vessels, which are echo-free and are elongated in at least one plane and show branches (Fig. 2) [32]. US has also been found useful as an imaging modality in monitoring response to anti-tubercular treatment in children [33]. Emerging reports of diagnostic utility of chest US in miliary tuberculosis [34] and human immunodeficiency virus (HIV) patients [35] hold promise for this radiation-free modality. Abdominal sonography should also be used as adjunct to thoracic US for detecting various abdominal and extrapulmonary manifestations of tuberculosis [16, 31]. Pericardial or pleural effusions, ascites and focal lesions in the liver or spleen are likely to be features of extrapulmonary tuberculosis where the disease is highly endemic [23]. In areas where HIVand tuberculosis co-infection is endemic, fast assessment with sonography for HIV/tuberculosis is especially useful. With this technique the thorax is evaluated and the liver and spleen are also assessed for disease involvement. The method is suitable for more rapid identification of extrapulmonary tuberculosis, even at hospitals where other imaging modalities are limited [23, 36]. Ultrasonography of mediastinum is performed using a suprasternal approach and a left parasternal approach (Fig. 2). Typically a high-resolution sector transducer (e.g., 7.5 MHz) is used. A lower-frequency (e.g., 5MHz) transducer can be used for deeper structures and older children. For suprasternal access, the child is asked to lie in supine position with 25–30° obliquity to the left side or in a supine decubitus position. Axial (coronal oblique) and sagittal oblique views of the anterior mediastinum can be obtained by placing the transducer first
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Fig. 2 Typical US findings in thoracic tuberculosis. a Intercostal US of the left lower chest and upper abdomen in a 6month-old infected with human immunodeficiency virus and disseminated tuberculosis demonstrates a left pleural effusion. b Intercostal US shows loculated organized fluid collection (asterisk) in the pleural space in a 6-year-old boy with persistent fever and chest pain. c Note the transducer position for mediastinal US in a child with suspected tuberculosis. The probe is rotated 90° for sagittal and coronal views. d Intercostal Color Doppler US of the chest in an 11year-old boy with thoracic tuberculosis using the suprasternal approach demonstrates mediastinal lymph nodes (arrow) that are separate from the mediastinal vessels (aortic arch and superior vena cava)
transversally at the suprasternal notch with inner (inferior) angulation and then rotating the transducer 90°. For the parasternal approach, the child is placed in a left lateral oblique position to increase the acoustic window, and axial and parasagittal views are obtained [31–33]. Limitations of using ultrasound include operator dependence and subjectivity, but these can be overcome with experience and procedure standardization.
Computed tomography CT is more sensitive than chest radiographs in detection of mediastinal and hilar lymphadenopathy and pleural and parenchymal disease and in assessment of complications (Fig. 3). CT can be used to identify enlarged lymph nodes in up to 60% of tuberculosis patients with normal chest radiographs [23]. CT is very useful in evaluating the complications of lymphobronchial tuberculosis in children, including the presence and degree of tracheal and bronchial compression, lobar collapse, bronchiectasis and pleural disease [37]. CT can also be used to differentiate tuberculous pleural infections from non-tuberculous pleural infections, with interlobular septal thickening and sub-pleural nodules being a characteristic feature of pleural tuberculosis [38]. Highresolution CT is recommended to detect centrilobular or miliary nodules, ground-glass opacities and mosaic perfusion,
while contrast-enhanced CT scan is helpful in assessing pleural components and diagnosis of empyema [16]. It is important to differentiate latent infection from active or confirmed tuberculous disease because this determines the course of treatment. Tuberculous disease can be missed if only chest radiography is used [39]. Chest CT has a reported detection rate of 80% in patients with active tuberculosis and 89% with inactive tuberculosis [20, 40]. Combined use of chest CT and interferon gamma release assay is considered more effective than the conventional approach of chest radiography and tuberculin skin test in differentiating among active infection, latent infection and non-infection [20, 40]. Characteristic findings on CT scan that are suggestive of active tuberculosis include the following [13, 16, 20]: (1) Lymphadenopathy: Enlarged lymph nodes in mediastinum or hilum with central necrosis (low attenuation central part) and a rim of peripheral enhancement. (2) Consolidation: Lobular pattern of consolidation favours tuberculosis but is nonspecific. Presence with an ipsilateral paratracheal or hilar lymphadenopathy favours tuberculosis. (3) Thick-walled pulmonary cavities. (4) Centrilobular nodules: These can be seen in a typical tree-in-bud appearance, which consists of multiple branching linear opacities. (5) Clustered and miliary nodules.
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Fig. 3 Typical findings at axial contrast-enhanced CT in thoracic tuberculosis. a, b Mediastinal and hilar necrotic and calcified lymph nodes (arrows) in an 8-year-old boy with thoracic tuberculosis. c Numerous diffuse tiny miliary nodules in a 10-year-old boy with disseminated tuberculosis. d Centrilobular nodules with branching
“tree-in-bud” pattern in an 8-year-old girl with clinically diagnosed tuberculosis. e Air-space nodules with cavitation (arrow) in a 12-yearold boy with culture-confirmed tuberculosis. f Right empyema (arrow) with collapse of the right lung in a 6-year-old boy with tuberculosis
Incorporation of chest CT in the diagnostic algorithm of children with suspected tuberculosis should be done keeping the overall risk–benefit aspect in mind [41]. CT is expensive and not readily available in lower-resource settings, and involves ionising radiation. Hence CT is not a standard imaging option [20, 23, 41]. It is useful in sputum-negative cases and children with radiographically equivocal or radiographically occult disease, and in high-risk groups (immunocompromised children) [41–43]. With rapid advances in CT technology and use of iterative models of reconstruction, sub-millisievert and ultra-low-dose CT are now performed without any significant compromise in image quality [44, 45]. Technological advances hold promise of performing a CT scan in children at doses at par with a conventional chest radiograph.
In pediatric tuberculosis, lymphadenopathy is the key imaging finding in making correct and early diagnosis (Fig. 4). In this context, thoracic MRI offers a great opportunity because it is comparable to multi-detector CT for detecting mediastinal lymph nodes. MRI yields sensitivity, specificity and positive and negative predictive values of 100% for the detection of mediastinal lymph nodes >7 mm in size [46]. MRI has also demonstrated perfect correlation with multi-detector CT in the detection of pulmonary consolidation, nodules (>3 mm), cyst/cavity and pleural effusions [46]. MRI has higher sensitivity for nodal involvement and pleural abnormalities in pulmonary tuberculosis than non-contrastenhanced CT scan [52, 53]. Signal intensity of tubercular nodes differs in different patients depending on the stage of disease and degree of evolution. High signal on T2-weighted images can indicate central or liquefactive necrosis, which is a typical radiologic feature of tuberculosis described at CT scan. These nodes have been predominantly described as slightly hyperintense to thoracic wall muscle, while a characteristic low T2 signal intensity of the necrotic lung parenchyma has been described in children with thoracic tuberculosis [54]. A simple robust chest MRI protocol would include nonrespiratory and non-electrocardiography-gated MRI sequences if the child is cooperative and can breath-hold. Free breathing or respiratory and cardiac-gated sequences can be performed depending on the clinical profile of the patient and
Magnetic resonance imaging MRI has recently emerged as a radiation-free alternative to CT for imaging children with pulmonary infections and compromised immune systems [46–51]. MRI seems useful in particular for follow-up and primary diagnosis in children, pregnant women and patients allergic to iodinated contrast media [52]. However MRI is expensive and often requires anaesthesia or monitored sedation. With technological advances in MRI and faster acquisition times, high-quality MRI of the lung is being developed and used in various clinical applications [46–49, 53].
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Fig. 4 Typical imaging features of tuberculosis on axial chest MRI. a Enlarged prevascular and paratracheal lymph nodes (arrows) in a 9-year-old girl with fever of 2 months’ with diagnosis of tuberculosis. b Thick-walled cavities (arrowheads) in both upper lobes in an 8-year-old boy with bacteriologically proven tuberculosis. c Consolidation (asterisk), centrilobular nodules (thin arrow), fibrocavitatory lesions (arrowhead) and lymph nodes (thick arrow) in an 11-yearold boy with bacteriologically confirmed tuberculosis. d Bilateral pleural effusion (arrows), larger on the right, in 8-year-old girl with thoracic tuberculosis who presented with fever and chest pain. e Left empyema (asterisk) with lung abscess/breakdown (arrow) in consolidated areas in a 10-yearold boy with thoracic tuberculosis
magnet time. Typically used axial MRI sequences include half-Fourier-acquisition single-shot turbo spin echo, steadystate free precession imaging, short tau inversion recovery spin echo and volumetric spoiled gradient echo [46–49]. Although contrast medium administration is not always required, it can be useful for detecting peripheral rim enhancement of lymph nodes. Unenhanced MRI does, however, demonstrate increased signal in necrotic tuberculous nodes (which are liquefied) on T2-weighted sequences. MRI can thus be employed for detection and follow-up of nodal and parenchymal disease in children with thoracic tuberculosis to reduce radiation exposure. To suggest disease activity, diffusion-weighted imaging (restricted diffusion in infected lymph nodes) and contrast administration (peripheral enhancement in caseating necrosis) can be performed. Its use in daily clinical practice is limited by cost and availability, especially in low-resource settings, but we advocate its use especially in patient follow-up at referral and academic centres. Future prospects include diffusion-weighted imaging, spectroscopic
analysis, chemical shift imaging and motion-corrected rapid MRI sequences, which can further improve the diagnostic utility of MRI in thoracic tuberculosis by suggesting diagnosis of tuberculosis without invasive tests and biopsies.
Positron emission tomography Many recent studies have described a role for positron emission tomography (PET), especially 18-fluorodeoxyglucose PET, as a noninvasive diagnostic method that can provide additional information regarding disease activity and guide management of tuberculous infections [55–58]. Active tuberculosis focus often shows increased uptake and when solitary can be mistaken for malignancy. Although it is now being increasingly used in the workup of patients in pyrexia of unknown origin, it can also be used to detect distant sites of involvement and can be used to guide biopsy from these active sites. However, low specificity, high radiation exposures,
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high cost factor and limited availability preclude the use of PET in clinical practice for a benign disease such as tuberculosis in children [56, 57].
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Role of the world Federation of Pediatric Imaging The World Federation of Pediatric Imaging seeks to create an impact in the global fight against childhood tuberculosis through the use of radiography in low-resource settings. The group emphasizes and delivers training and education on tuberculosis imaging through site visits, regional training exchanges, international training courses and webinars [59, 60]. Through the World Federation of Pediatric Imaging website, tuberculosis experts release instructional videos and lectures on the interpretation of chest radiographs in children suspected of having tuberculosis. Understanding the importance and magnitude of this disease, the federation has assembled experts from high-tuberculosis-burden countries in Africa, Asia and Latin America in an attempt to impact childhood tuberculosis imaging diagnosis in lower-resource settings. The group makes open-access educational articles on tuberculosis freely available for wide dissemination [59, 60].
Conclusion
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Despite some limitations and low specificity, chest radiography continues to be the key imaging modality used in diagnosis of thoracic tuberculosis in children. CT and MRI are often performed for clinically diagnosed tuberculosis and detection of various complications. MRI and US should be used for mediastinal lymph node detection where infrastructure and expertise is available because these modalities do not involve radiation risks. In low-resource settings where CT and MRI are not available, chest radiography and US hold the fort for radiology. For the future, advances in imaging technology hold promise to perform faster and more accurate crosssectional imaging with no more radiation risks than a conventional radiograph. Judicious and optimum use of available imaging resources should be performed to obtain best results in fighting the disease.
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