{"chunks": ["/gid00030/gid00035/gid00032/gid00030/gid00038/gid00001/gid00033/gid00042/gid00045/gid00001 /gid00048/gid00043/gid00031/gid00028/gid00047/gid00032/gid00046 Citation: Nel, M.; Franckling-Smith, Z.; Pillay, T.; Andronikou, S.; Zar, H.J. Chest Imaging for Pulmonary TB\u2014An Update. Pathogens 2022, 11, 161. https://doi.org/10.3390/ pathogens11020161 Academic Editors: Steve M Graham, Ben J. Marais and Farhana Amanullah Received: 1 December 2021 Accepted: 21 January 2022 Published: 26 January 2022 Publisher\u2019s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional af\ufb01l- iations. Copyright: \u00a9 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pathogens Review Chest Imaging for Pulmonary TB\u2014An Update Michael Nel 1 , Zoe Franckling-Smith 1, Tanyia Pillay 2, Savvas Andronikou 3 and Heather J. Zar 1,* 1 Department of Paediatrics and Child Health, Red Cross War Memorial Children\u2019s Hospital, and The SA-MRC Unit on Child and Adolescent Health, University of Cape Town, Cape Town 8001, South Africa; michaelnel6@gmail.com (M.N.); zoe.franckling-smith@uct.ac.za (Z.F.-S.) 2 Department of Radiology, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, South Africa; tanyiapillay@gmail.com 3 Department of Radiology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA; doctor.andronikou@gmail.com * Correspondence: heather.zar@uct.ac.za Abstract: The diagnosis of pulmonary tuberculosis (PTB) in children is challenging. Dif\ufb01culties in acquiring suitable specimens, pauci-bacillary load, and limitations of current diagnostic methods often make microbiological con\ufb01rmation dif\ufb01cult. Chest imaging provides an additional diagnostic modality that is frequently used in clinical practice. Chest imaging can also provide insight into treatment response and identify development of disease complications. Despite widespread use, chest radiographs are usually non-speci\ufb01c and have high inter- and intra-observer variability. Other diagnostic imaging modalities such as ultrasound, computed tomography (CT), and magnetic reso- nance imaging (MRI) can provide additional information to substantiate diagnosis. In this review, we discuss the radiological features of PTB in each modality, highlighting the advantages and limitations of each. We also address newer imaging technologies and potential use. Keywords: tuberculosis; chest imaging; children; X-ray; ultrasound; computed tomography; mag- netic resonance imaging 1. Introduction The diagnosis of pulmonary tuberculosis (PTB) remains a challenge, especially in young children in whom non-speci\ufb01c clinical presentation, dif\ufb01culty in collecting ade- quate samples for microbiologic testing, and pauci-bacillary load can result in diagnostic uncertainty. Chest imaging provides a useful tool to support the clinical diagnosis. However, chest imaging as a diagnostic tool for paediatric PTB has speci\ufb01c challenges depending on the modality used, including poor inter-observer reliability, non-speci\ufb01c", "radiological signs, and lack of standardized scoring or classi\ufb01cation systems . This paper aims to review the different radiographic modalities and features for diagnosis of paediatric PTB, their use and limitations, as well as newer imaging techniques. 2. Overview of Imaging Techniques Available Chest radiographs are the primary radiologic investigation in children for diagnosis and assessment of PTB . Radiograph \ufb01ndings closely re\ufb02ect the pathophysiology of the disease (Table 1) . Parenchymal foci associated with lymphadenopathy (Ghon complex) are often small and dif\ufb01cult to identify on chest radiograph . Despite the reliance on radiographs in the diagnosis of paediatric PTB, poor sensitivity, speci\ufb01city, and wide inter observer agreement have been demonstrated . Sensitivity of chest radiography for detecting lymphadenopathy, when compared against CT imaging, has been shown to be 67\u201374%, with a speci\ufb01city of 39\u201359% . The use of the lateral radiograph in improving sensitivity or speci\ufb01city is controversial. One study found that a lateral radiograph in addition to a frontal image did not signi\ufb01cantly improve the diagnostic yield, but increased cost and radiation exposure . In another study, a moderate correlation between \ufb01ndings Pathogens 2022, 11, 161. https://doi.org/10.3390/pathogens11020161 https://www.mdpi.com/journal/pathogens", "Pathogens 2022, 11, 161 2 of 15 of lymphadenopathy on lateral chest radiograph and CT scan was shown, with precarinal lymph nodes associated with the highest sensitivity and speci\ufb01city . The detection of lymphadenopathy on chest radiographs has signi\ufb01cant inter-observer variability (average weighted kappa of 0.33\u20130.36) and poor intra-observer agreement (average weighted kappa of 0.55) . Table 1. Advantages and disadvantages of commonly available imaging modalities. Imaging Modality Advantages Disadvantages Chest radiograph Widespread availability Low dose ionizing radiation Cost effective Poor intra- and inter-observer agreement Poor sensitivity/speci\ufb01city Ultrasound Performed at bedside Requires user experience Free of ionizing radiation Detects mediastinal nodes or pleural effusion before CXR Ability to assess for extrapulmonary TB Sensitivity/speci\ufb01city data for signs still scanty Unable to assess pulmonary hila for lymphadenopathy Computed tomography (CT) Earlier more sensitive detection of TB disease and complications compared with CXR Expensive Requires speci\ufb01c expertise Ability to monitor disease complications and treatment response Ionizing radiation although low dose protocols now in use Higher sensitivity for detecting nodes Allows for surgical planning Characterization of lymph node morphology and enhancement May differentiate TB from non-TB lymphadenopathy Limited availability May require contrast Magnetic resonance Imaging (MRI) Sensitivity/speci\ufb01city comparable to CT (except small nodules/GGO) Differentiate TB lymphadenopathy from reactive lymph nodes based on signal intensity and heterogeneity Expensive Requires speci\ufb01c expertise Limited availability May require sedation/anesthesia Longer scanning times (relative to other modalities) A chest ultrasound offers a portable, non-invasive, and real-time assessment of in- trathoracic pathology without the use of ionizing radiation. Ultrasound allows trained clinicians to make prompt diagnostic and management decisions at the bedside. A major advantage of ultrasound is the ability to assess for features of extrapulmonary TB including ascites, hepatic micro abscesses, pericardial effusion or abdominal lymph nodes. Ultra- sound abnormalities suggestive of PTB (consolidation, pleural effusion, or lymphadenopa- thy) may be found in 31 to 83% of con\ufb01rmed cases with high inter-reader agreement . Diagnostic accuracy increases with user experience . However, data on the sensitiv- ity and speci\ufb01city of ultrasound for PTB in children are still scanty. Most studies have compared ultrasound with chest radiograph \ufb01ndings. This makes the assessment of diag- nostic accuracy dif\ufb01cult due to the poor accuracy of chest radiographs. The use of clinical diagnosis as a reference standard is similarly \ufb02awed. Comparison with gold standard imaging techniques, such as CT scanning, would provide valuable information regarding the usefulness of ultrasound in the diagnosis and", "management of PTB. CT scanning is regarded as the \u201cgold standard\u201d for imaging of primary pulmonary TB in children. Cross-sectional images as well as 3D image processing provide excellent anatomical detail and bypass the problem of superimposition of anatomical structures in chest radiographs. CT scanning allows for earlier and more frequent detection of", "Pathogens 2022, 11, 161 3 of 15 lymphadenopathy, consolidation or pleural effusion when compared with chest radio- graphs . Beyond this, CT allows for more accurate assessment of disease process, activity, and detection of complications . CT is particularly good for characterizing lymph nodes. The presence of calci\ufb01cation, although uncommon, within a lymph node is highly suggestive of TB . The pattern of enhancement of lymphadenopathy can distinguish PTB from other diseases. TB nodes typically either ring enhance (indicating a central core of caseous necrosis) or exhibit \u2018ghost-like\u2019 enhancement within a matted mass of indiscrete nodes . Lung parenchymal complications distal to lymph node compression follow a pre- dictable stepwise course . These features can be staged with CT and determine whether lung is salvageable or non-salvageable . Staging can guide medical therapy and deter- mine whether surgical intervention is required, such as enucleation of offending lymph nodes or lobectomy of a non-salvageable lung. In addition, CT of the chest has the potential to detect features of extrapulmonary TB. The pleura, pericardium, chest wall, spine, and the upper portions of the liver and spleen are visualized in a standard chest CT. There has been a reluctance for widespread use of CT scanning in children due to the perceived risk of ionizing radiation exposure. Advances in CT imaging techniques, such as the use of extended detector row multi-detector CT scanners, dose modulation, iterative reconstruction, and speci\ufb01c paediatric scanning protocols, have led to a large reduction in ionizing radiation dose . These images can be acquired rapidly without the need for breath holding, reducing the need for procedural sedation and physical constraints . A case report demonstrates the use of low-dose CT scanning to monitor the response to extensively drug resistant TB treatment . The effective dose for each CT in this case was 0.4\u20130.7 mSv which is equivalent to \u00b13 months of background radiation exposure . This is much lower than previously documented doses of \u00b1 8.8mSv per scan . Magnetic Resonance Imaging (MRI), although more expensive and less widely avail- able than other imaging modalities, is free from ionizing radiation [ 2,21\u201323] and is an ideal investigation for follow-up [21\u201323]. MRI long acquisition times in the past required children to have sedation or anesthesia for the procedure. However, the development of rapid MRI sequences, with acquisition times of 10\u201320s per sequence , have made MRI a more attractive investigation, especially", "in children, which is achievable without sedation . MRI is equivocal to CT in diagnosing primary pulmonary TB in children . 3. Imaging Findings in Relation to TB Disease Primary TB Following an incubation period, during which the chest radiograph is typically normal, hilar or mediastinal lymphadenopathy occur as part of primary disease (Table 2) . Regional lymphadenopathy is the radiological hallmark of paediatric PTB, with right hilar and right paratracheal regions predominating . Nodal enlargement is present in 91\u2013100% of PTB cases in children under 5 years, with the prevalence decreasing with increasing age . Right hilar adenopathy (a lobulated hilar opacity on chest radiograph) obscuring the hilar point, Figure 1, is more commonly observed than left, with left hilar nodes only evident when extending beyond the left cardiac border . Paratracheal adenopathy may be dif\ufb01cult to distinguish from other mediastinal tissues, such as the thymus, but will extend beyond the normal mediastinal contours, and may result in airway compression and deviation . Left paratracheal lymphadenopathy is rarely observed in isolation, most commonly co-existing alongside other regions of mediastinal lymphadenopathy . Sub- or retro-carinal lymphadenopathy is typically seen on the lateral projection as lobulated densities inferior and posterior to the bronchus intermedius, which, in combination with the more superior aortic arch and pulmonary arteries result in the well described \u201cdoughnut sign\u201d (Figure 2).", "Pathogens 2022, 11, 161 4 of 15 Table 2. Imaging \ufb01ndings for each form of PTB. Form of PTB Imaging Findings Comments Primary TB Lymphadenopathy CXR: Lobulated hilar/paratracheal opacity. Potential for airway attenuation or deviation. Doughnut sign on lateral radiograph. US: Well de\ufb01ned round/oval hypoechoic (to thymic tissue and fat) nodes within the anterior and superior mediastinum. CT: Typically, low attenuation centrally with peripheral rim enhancement of node post contrast administration. Alternatively, matted conglomerate with \u2018ghost-like\u2019 rim enhancement. MRI: Low T2/STIR signal intensity nodes. Post gadolinium T1 images may demonstrate rim enhancement. Right sided lymphadenopathy more common than left. CXR typically normal during incubation period. US unable to assess hilar region. CT detects nodes in a signi\ufb01cant proportion of patients with normal CXR. Central low attenuation with peripheral enhancement helps distinguish from non-TB adenopathy. MRI comparable to CT in node detection over 3 mm. Primary progressive TB Progressive adenopathy CXR: Airway compression or displacement most reliable \ufb01nding. Attenuation can result in distal ipsilateral hyperin\ufb02ation, atelectasis or consolidation. US: Unable to assess airway compression but may detect distal complications. CT: Smooth luminal narrowing indicates extrinsic compression. Irregular narrowing may indicate erosion into lumen. Excellent for identifying complications, planning treatment and monitoring treatment response. MRI: Detection of compressive nodes and distal complications comparable to CT. Poorer resolution (in comparison with CT) makes airway lumen assessment and exact nodal location identi\ufb01cation dif\ufb01cult. Airspace disease CXR: Opaci\ufb01cation of lung parenchyma silhouetting adjacent structures. May display air bronchograms. US: Comparable detection rates to CXR with peripheral consolidation. Able to identify <0.5cm consolidation (usually undetectable on CXR). CT: Classic \u2018tree-in-bud\u2019 pattern. Central low attenuation non-enhancing regions represent caseous necrosis. MRI: Able to characterize TB consolidation. Consolidation in viable lung tissue demonstrates intermediate-to-high STIR signal. Low signal on STIR sequence indicates necrotic lung tissue. Miliary TB Younger children more likely to develop nodal airway compression due to inherently narrower airways and weaker cartilaginous support structures. Airway attenuation is the most reliable CXR sign. Distal complications of airway compression include atelectasis, air-trapping, consolidation, necrosis and breakdown. Airway attenuation and characterization of complications better characterized by CT and MRI. Miliary TB best identi\ufb01ed by presence of diffuse small nodules and thickened septal lines. CT is the superior imaging technique. CXR: Often normal. Diffuse small non-calci\ufb01ed nodules. Thickened interlobular septal lines. US: No sensitive \ufb01ndings in children yet described. CT: Miliary nodules visualized well before visible on CXR. Small (<3", "mm) randomly distributed nodules with thickened interlobular septa. MRI: Unable to detect <3 mm nodules. Useful in detecting lesions in solid organs (liver/spleen) Post primary TB Cavitation CXR: Often dif\ufb01cult to distinguish small cavity from consolidation. Airspace opaci\ufb01cation surrounding an area of cavitation represents central caseous necrosis and liquefaction. Air-\ufb02uid level may represent secondary infection. CT: Central low-attenuating cavity. Cavity wall variable in size. Cavity surrounded by consolidation. MRI: Low signal cavity with surrounding consolidation. Cavity formation is the hallmark of post-primary TB. Small cavities easily missed on CXR. CT and MRI superior to CXR in the detection of cavities. Usually predominate in upper lobes or apical segments of lower lobes. More common in adolescents. CT is useful in assessing cavity wall thickness.", "Pathogens 2022, 11, 161 5 of 15 Pathogens 2022, 11, x FOR PEER REVIEW 5 of 16 central caseous necrosis and liquefaction. Air-fluid level may rep- resent secondary infection. CT: Central low-attenuating cavity. Cavity wall variable in size. Cavity surrounded by consolidation. MRI: Low signal cavity with surrounding consolidation. cavities. Usually predominate in up- per lobes or apical segments of lower lobes. More common in ado- lescents. CT is useful in assessing cavity wall thickness. Right hilar adenopathy (a lobulated hilar opacity on chest radiograph) obscuring the hilar point, Figure 1, is more commonly observed than left, with left hilar nodes only evi- dent when extending beyond the left cardia c border . Paratracheal adenopathy may be difficult to distinguish from other mediastinal tissues, such as the thymus, but will extend beyond the normal mediastinal contours, and may result in airway compression and deviation . Left paratracheal ly mphadenopathy is rarely observed in isolation, most commonly co -existing alongside other regions of mediastinal lymphadenopathy . Sub- or retro-carinal lymphadenopathy is typically seen on the lateral projection as lobulated densities inferior and post erior to the bronchus intermedius, which, in combi- nation with the more superior aortic arch and pulmonary arteries result in the well de- scribed \u201cdoughnut sign.\u201d Figure 2. (a) (b) Figure 1. (a,b): Right Paratracheal and Hilar lymphadenopathy before and after treatment. ( a) AP chest radiograph of a child at presentation, who later was later confirmed to have pulmonary TB, demonstrates a right-sided lobulated cardio-mediastinal margin with filling of the right hilar point (white arrows) and consistent with right paratracheal and hilar lymphadenopathy. The trachea is displaced to the left, slightly bowed and shows decreased calibre just superior to the carina. There is an oval density seen separately from the scapula in the right lung apex, which in conjunction with the lymphadenopathy, constitutes the Ghon Complex. ( b) Post-treatment AP chest radiograph demonstrates complete resolution of the parenchymal focus and lymphadenopathy with a normal right cardio-mediastinal border and return of the trachea to its normal shape and position. Figure 1. (a,b): Right Paratracheal and Hilar lymphadenopathy before and after treatment. (a) AP chest radiograph of a child at presentation, who later was later con\ufb01rmed to have pulmonary TB, demonstrates a right-sided lobulated cardio-mediastinal margin with \ufb01lling of the right hilar point (white arrows) and consistent with right paratracheal and hilar lymphadenopathy. The trachea is displaced to the", "left, slightly bowed and shows decreased calibre just superior to the carina. There is an oval density seen separately from the scapula in the right lung apex, which in conjunction with the lymphadenopathy, constitutes the Ghon Complex. (b) Post-treatment AP chest radiograph demonstrates complete resolution of the parenchymal focus and lymphadenopathy with a normal right cardio-mediastinal border and return of the trachea to its normal shape and position. Pathogens 2022, 11, x FOR PEER REVIEW 6 of 16 (a) (b) Figure 2. (a,b): Left hilar lymphadenopathy on the PA and lateral chest radiographs. ( a) PA erect chest radiograph in this child with later confirmed pulmonary TB demonstrates a multilobulated lymph node mass projecting beyond the cardiac margin on the left (white arrows) consistent with left hilar lymphadenopathy. There is also loss of the left cardiac margin consistent with lingula air- space disease/atelectasis as a consequence of left main bronchus compression (black arrow). (b) Lat- eral chest radiograph confirms the presence of hilar lymphadenopathy by demonstrating an oval mass consistent with the \u2018doughnut sign\u2019 (curved white a rrows), representing lymphadenopathy inferiorly and likely the normal vessels (aortic arch and left main pulmonary artery) superiorly. Ultrasound examination\u2014via the suprasternal notch window\u2014can be used to iden- tify anterior mediastinal lymphadenopathy. These lymph nodes appear as round or oval- shaped, well-defined structures visible in the anterior and superior mediastinum usually surrounded by thymic tissue or mediastinal vessels . Lymph nodes are hypoechoic compared with thymic tissue and mediasti nal fat and hyperechoic compared with sur- rounding blood vessels . Ultrasound may also be useful to monitor treatment response . In one study, 67% of tuberculin-skin-test-positive children with normal chest X-rays had enlarged lymph nodes detectable via mediastinal ultrasound . Ultrasound more commonly detects mediastinal lymphadenopathy than plain chest radiographs with su- perior inter-reader agreement . Despite this, the specificity of enlarged mediastinal lymph nodes is uncertain. Lymph nod es were identified in all groups of children (con- firmed TB, suspected TB, and unlikely TB) with significantly larger nodes (>1.1 cm) seen in confirmed and suspected cases over those seen in unlikely TB cases . This suggests the need for an agreed lymph node size cut off to distinguish PTB from other infections. CT can identify lymphadenopathy in a significant proportion of children with PTB and normal chest radiographs . On post-contrast CT, TB lymphadenopathy typically appears as having low attenuation centrally with peripheral", "rim enhancement (Figure 3). The central region of low attenuation represents caseous necrotic tissue seen in tuber- culous lymphadenopathy, enabling this to be distinguished from non-TB adenopathy. Al- ternatively, TB nodes may form a matted conglomerate with \u2018ghost-like\u2019 rim enhancement . Moderately enlarged lymph nodes may occur in bacterial pneumonia, but rarely hav- ing areas of necrosis or calcification . Figure 2. (a,b): Left hilar lymphadenopathy on the PA and lateral chest radiographs. ( a) PA erect chest radiograph in this child with later con\ufb01rmed pulmonary TB demonstrates a multilobulated lymph node mass projecting beyond the cardiac margin on the left (white arrows) consistent with left hilar lymphadenopathy. There is also loss of the left cardiac margin consistent with lingula air-space disease/atelectasis as a consequence of left main bronchus compression (black arrow). (b) Lateral chest radiograph con\ufb01rms the presence of hilar lymphadenopathy by demonstrating an oval mass consistent with the \u2018doughnut sign\u2019 (curved white arrows), representing lymphadenopathy inferiorly and likely the normal vessels (aortic arch and left main pulmonary artery) superiorly. Ultrasound examination\u2014via the suprasternal notch window\u2014can be used to identify anterior mediastinal lymphadenopathy. These lymph nodes appear as round or oval- shaped, well-de\ufb01ned structures visible in the anterior and superior mediastinum usually", "Pathogens 2022, 11, 161 6 of 15 surrounded by thymic tissue or mediastinal vessels . Lymph nodes are hypoe- choic compared with thymic tissue and mediastinal fat and hyperechoic compared with surrounding blood vessels . Ultrasound may also be useful to monitor treatment response . In one study, 67% of tuberculin-skin-test-positive children with normal chest X-rays had enlarged lymph nodes detectable via mediastinal ultrasound . Ultrasound more commonly detects mediastinal lymphadenopathy than plain chest radiographs with supe- rior inter-reader agreement . Despite this, the speci\ufb01city of enlarged mediastinal lymph nodes is uncertain. Lymph nodes were identi\ufb01ed in all groups of children (con\ufb01rmed TB, suspected TB, and unlikely TB) with signi\ufb01cantly larger nodes (>1.1 cm) seen in con\ufb01rmed and suspected cases over those seen in unlikely TB cases . This suggests the need for an agreed lymph node size cut off to distinguish PTB from other infections. CT can identify lymphadenopathy in a signi\ufb01cant proportion of children with PTB and normal chest radiographs . On post-contrast CT, TB lymphadenopathy typically appears as having low attenuation centrally with peripheral rim enhancement (Figure 3). The central region of low attenuation represents caseous necrotic tissue seen in tuberculous lymphadenopathy, enabling this to be distinguished from non-TB adenopathy. Alterna- tively, TB nodes may form a matted conglomerate with \u2018ghost-like\u2019 rim enhancement . Moderately enlarged lymph nodes may occur in bacterial pneumonia, but rarely having areas of necrosis or calci\ufb01cation . Pathogens 2022, 11, x FOR PEER REVIEW 7 of 16 (a) (b) Figure 3. (a,b): Lymphadenopathy, air-space disease and airway compression on chest radiograph and CT. ( a) Frontal AP chest radiograph in a 14 -month-old boy with confirmed pulmonary TB demonstrating right hilar and paratracheal lymphadenopathy as lobulated masses projecting from the right of the cardio-mediastinal shadow (white arrows). There is also air-space disease in the right upper lobe, tracheal compression (black arrow) and left main bronchus compression (curved black arrow), resulting from presumed subcarinal and left hilar lymphadenopathy. (b) Axial post-contrast CT scan confirming the right paratracheal lymphadenopathy which has a low -density centre and fine rim enhancement (white arrow) and AP compression of the trachea (black arrow), which was not appreciated on the AP radiograph. MRI is comparable to CT in the detection of lymph nodes >3mm . However, due to the lower spatial resolution, MRI is unable to detect small lymph nodes <3mm. Normal lung parenchyma on MRI has a low", "signal and MRI is poorer at detecting subtle abnor- malities such as ground glass opacification and mosaic attenuation . MRI can, how- ever, further differentiate TB lymphadenopathy from reactive lymph nodes based on sig- nal intensity and heterogeneity. The presence of enhancement post contrast suggests ac- tive disease . Short Tau inversion recovery (STIR) / T2 -weighted MRI sequences may demonstrate characteristic low signal in TB lymphadenopathy and parenchymal ne- crosis (Figure 4). Figure 4. (a\u2013h): Coronal, sagittal and axial MRI in a 6 -year-old girl with confirmed pulmonary TB. Coronal (a\u2013c) and sagittal STIR ( d,e) images demonstrate characteristic low signal TB lymphade- nopathy (white arrows) in the right and left paratracheal, and hilar regions. These can be compared Figure 3. (a,b): Lymphadenopathy, air-space disease and airway compression on chest radiograph and CT. ( a) Frontal AP chest radiograph in a 14-month-old boy with con\ufb01rmed pulmonary TB demonstrating right hilar and paratracheal lymphadenopathy as lobulated masses projecting from the right of the cardio-mediastinal shadow (white arrows). There is also air-space disease in the right upper lobe, tracheal compression (black arrow) and left main bronchus compression (curved black arrow), resulting from presumed subcarinal and left hilar lymphadenopathy. (b) Axial post-contrast CT scan con\ufb01rming the right paratracheal lymphadenopathy which has a low-density centre and \ufb01ne rim enhancement (white arrow) and AP compression of the trachea (black arrow), which was not appreciated on the AP radiograph. MRI is comparable to CT in the detection of lymph nodes >3 mm . However, due to the lower spatial resolution, MRI is unable to detect small lymph nodes <3 mm. Normal lung parenchyma on MRI has a low signal and MRI is poorer at detecting subtle abnormalities such as ground glass opaci\ufb01cation and mosaic attenuation . MRI can, however, further differentiate TB lymphadenopathy from reactive lymph nodes based on signal intensity and heterogeneity. The presence of enhancement post contrast suggests active disease . Short Tau inversion recovery (STIR)/T2-weighted MRI sequences may demonstrate characteristic low signal in TB lymphadenopathy and parenchymal necrosis (Figure 4).", "Pathogens 2022, 11, 161 7 of 15 Pathogens 2022, 11, x FOR PEER REVIEW 7 of 16 (a) (b) Figure 3. (a,b): Lymphadenopathy, air-space disease and airway compression on chest radiograph and CT. ( a) Frontal AP chest radiograph in a 14 -month-old boy with confirmed pulmonary TB demonstrating right hilar and paratracheal lymphadenopathy as lobulated masses projecting from the right of the cardio-mediastinal shadow (white arrows). There is also air-space disease in the right upper lobe, tracheal compression (black arrow) and left main bronchus compression (curved black arrow), resulting from presumed subcarinal and left hilar lymphadenopathy. (b) Axial post-contrast CT scan confirming the right paratracheal lymphadenopathy which has a low -density centre and fine rim enhancement (white arrow) and AP compression of the trachea (black arrow), which was not appreciated on the AP radiograph. MRI is comparable to CT in the detection of lymph nodes >3mm . However, due to the lower spatial resolution, MRI is unable to detect small lymph nodes <3mm. Normal lung parenchyma on MRI has a low signal and MRI is poorer at detecting subtle abnor- malities such as ground glass opacification and mosaic attenuation . MRI can, how- ever, further differentiate TB lymphadenopathy from reactive lymph nodes based on sig- nal intensity and heterogeneity. The presence of enhancement post contrast suggests ac- tive disease . Short Tau inversion recovery (STIR) / T2 -weighted MRI sequences may demonstrate characteristic low signal in TB lymphadenopathy and parenchymal ne- crosis (Figure 4). Figure 4. (a\u2013h): Coronal, sagittal and axial MRI in a 6 -year-old girl with confirmed pulmonary TB. Coronal (a\u2013c) and sagittal STIR ( d,e) images demonstrate characteristic low signal TB lymphade- nopathy (white arrows) in the right and left paratracheal, and hilar regions. These can be compared Figure 4. (a\u2013h): Coronal, sagittal and axial MRI in a 6-year-old girl with con\ufb01rmed pulmonary TB. Coronal (a\u2013c) and sagittal STIR (d,e) images demonstrate characteristic low signal TB lymphadenopa- thy (white arrows) in the right and left paratracheal, and hilar regions. These can be compared with the higher signal axillary lymph nodes in image (c) which represent the appearance of non-TB nodes. Axial post gadolinium T1 at the level of the aortic arch ( f) demonstrates that the STIR low signal lymphadenopathy in (a\u2013e) demonstrates rim enhancement (white arrows), typical of centrally necrotic TB nodes. In addition, there is homogenous enhancement of a dense left consolidation (star) with", "an area of non-enhancing low signal (black arrow), in keeping with parenchymal breakdown within the consolidation. The axial STIR (g) and corresponding gadolinium enhanced T1 (h) at the lower zone of the lungs demonstrates an intermediate-to-high STIR signal enhancing consolidation posteriorly on the right (star) in keeping with viable lung; an intermediate STIR signal, poorly and heterogeneously enhancing consolidation on the left (star) in keeping with at risk lung; and a T2 low STIR signal non-enhancing focal area on the left (black arrow) typical of TB necrosis (this is the opposite to the STIR signal of an abscess, which would be bright). 4. Primary Progressive TB 4.1. Progressive Adenopathy/Lymphotracheobronchial TB Disruption of airways by tuberculous lymph nodes and the subsequent parenchymal complications de\ufb01ne lymphotracheobronchial TB. Younger children are more likely to develop lymphotracheobronchial TB as they have a higher prevalence of lymphadenopa- thy , smaller bronchial lumen diameter, and weaker cartilaginous support structures compared with adults. Common complications of nodal compression include air-trapping, atelectasis, consolidation, expansile pneumonia, necrosis, or breakdown . The bronchus intermedius is the most commonly involved, likely because it is longer and narrower than the second order bronchi and is situated between right hilar and sub-carinal nodes . Airway compression is the most reliable chest radiograph feature of lymphadenopathy . The trachea can be displaced, or attenuated by paratracheal lymphadenopathy . On a chest radiograph, compression of airways can result in ipsilateral hyperin\ufb02ation and atelectasis, or \u201ccollapse-consolidation\u201d . High-kilovolt (KV) frontal radiographs have been used to better demonstrate the tracheobronchial tree, and the compressive effects of lymphadenopathy in children . However, the addition of high-kV radiographs to standard radiographs has not been shown to signi\ufb01cantly increase the sensitivity (38% vs. 38.8%, respectively) or speci\ufb01city (86% vs. 74.4%, respectively) in detecting PTB amongst patients with microbiologically con\ufb01rmed TB . Furthermore, the cost of imaging may increase as much as 45% if high-kV imaging is performed . It is thus recommended that high-kV imaging is used to better demonstrate", "Pathogens 2022, 11, 161 8 of 15 airway attenuation only in select cases of persistent collapse, when CT scans are not readily available . CT is an excellent tool for assessing the airways and identifying multifocal, segmental areas of air-trapping, atelectasis, and consolidation . Additionally, CT can help to determine the cause of tracheobronchial attenuation . Extrinsic compression of a bronchus by an adjacent lymph node causes smooth luminal narrowing. Figure 5. This can create a ball valve phenomenon leading to distal air-trapping. Complete occlusion of the lumen can then result in atelectasis or consolidation and progress to necrosis and cavitation if left untreated . Irregular bronchial lumen narrowing may indicate erosion of an adjacent node into the lumen . Pathogens 2022, 11, x FOR PEER REVIEW 9 of 16 (a) (b) (c) Figure 5. (a\u2013c): Lymphobronchial TB. Chest radiograph and CT in a 13 -month-old boy with con- firmed pulmonary TB: (a) The frontal AP chest radiograph is suggestive of bilateral hilar and para- tracheal lymphadenopathy by the presence of bronchus intermedius and left main bronchus com- pressions resulting in bilateral (black arrows), mid and lower zone air -trapping. (b) Axial, post- contrast, soft -tissue-windowed CT scan at the level of the pulmonary trunk bifurcation demon- strates extensive subcarinal and hilar lymphadenopathy (black arrows) with marked bronchus in- termedius attenuation (white arrow). (c) Coronal reconstruction of the post-contrast soft-tissue-win- dowed CT scan demonstrates paratracheal, sub-carinal and hilar lymphadenopathy (stars). There is attenuation of the bronchus intermedius and the left main bronchus (white arrows). There is also a suggestion of erosion of a right hilar lymph node into the lumen of the bronchus intermedius (black arrow). 4.2. Airspace Disease Consolidation can occur via several distinct mechanisms. Firstly, it may represent primary parenchymal PTB disease, which then spreads to regional lymph nodes. Con- versely, in primary progressive TB disease, consolidation can develop as a complication of airway compression or from bronchogenic spread of disease . Consolidation is characterized on chest radiographs by air bronchograms and silhouetting of the cardiac, mediastinal, or diaphragmatic margins, depending on the location (Figure 6). Figure 5. (a\u2013c): Lymphobronchial TB. Chest radiograph and CT in a 13-month-old boy with con\ufb01rmed pulmonary TB: (a) The frontal AP chest radiograph is suggestive of bilateral hilar and paratracheal lymphadenopathy by the presence of bronchus intermedius and left main bronchus compressions resulting in bilateral (black arrows), mid and lower zone air-trapping.", "(b) Axial, post-contrast, soft- tissue-windowed CT scan at the level of the pulmonary trunk bifurcation demonstrates extensive subcarinal and hilar lymphadenopathy (black arrows) with marked bronchus intermedius attenu- ation (white arrow). (c) Coronal reconstruction of the post-contrast soft-tissue-windowed CT scan demonstrates paratracheal, sub-carinal and hilar lymphadenopathy (stars). There is attenuation of the bronchus intermedius and the left main bronchus (white arrows). There is also a suggestion of erosion of a right hilar lymph node into the lumen of the bronchus intermedius (black arrow).", "Pathogens 2022, 11, 161 9 of 15 The anatomic detail of CT allows for accurate assessment of lymph node compression. Multiplanar reconstruction\u2014especially coronal thick slab minimum intensity projection\u2014 allows assessment of the large airway in its entirety. Three-dimensional volumetric render- ing adds further accuracy with the ability to measure stenosis length and predict whether the offending node is endobronchial, submucosal, or peri-bronchial . These techniques provide a virtual road map for the monitoring of treatment response, identi\ufb01cation of com- plications, bronchoscopy, and precise surgical planning if enucleation of a node is required. 4.2. Airspace Disease Consolidation can occur via several distinct mechanisms. Firstly, it may represent pri- mary parenchymal PTB disease, which then spreads to regional lymph nodes. Conversely, in primary progressive TB disease, consolidation can develop as a complication of airway compression or from bronchogenic spread of disease . Consolidation is characterized on chest radiographs by air bronchograms and silhouetting of the cardiac, mediastinal, or diaphragmatic margins, depending on the location (Figure 6). Pathogens 2022, 11, x FOR PEER REVIEW 10 of 16 (a) (b) Figure 6. Consolidation and miliary TB. Frontal AP and lateral chest radiographs in a 3 -year-old boy with confirmed disseminated TB. This child did not receive BCG vaccination. ( a) Frontal AP and ( b) lateral chest radiographs demonstrating righ t upper lobe consolidation with air bron- chograms (black arrow) limited by the horizontal fissure (white arrows), as well as parenchymal miliary TB nodules. The ability to identify peripheral consolidation with ultrasound is comparable to chest radiographs . This is consistent with previous pneumonia studies . Small consolidation (<0.5 cm), usually not identified on chest radiographs, is more frequently seen when using ultrasound . Children over 5 years more commonly exhibit \u201ctree -in-bud\u201d consolidation on CT scan. This represents multiple areas of centrilobular nodules . As the disease pro- gresses, consolidation may develop areas of caseous necrosis centrally \u2014this is repre- sented by areas of low attenuation which do not enhance post-administration of contrast. Rarely, airspace disease progresses to cavity formation, as is commonly seen in adult TB . MRI is superior to CT in the characterization of tuberculous consolidation in that the MRI signal varies with the stage of necrosis and the p resence of mycobacterium within the necrosis . Caseous necrosis in TB consolidation demonstrates a characteristic low signal on T2-weighted sequences and is an indicator of active TB [Figure 4]. 4.3.", "Miliary TB Miliary TB is more common in young or immunocompromised patients occurring secondary to hematogenous spread of the disease. It is characterized on the chest radio- graph by the diffusion of small (<2 mm) non-calcified nodules, representing granulomas, appearing throughout the lung parenchyma, frequently in combination with thickened interlobular septal lines (Figure 6). However, in 25\u201340% of cases, chest radiographs are normal . Miliary nodules occur on CT well before they become visible on chest radio- graphs . 5. Post Primary TB Cavitation Post-primary cavitation is seen more commonly in adolescents and is the hallmark of post-primary TB on chest radiographs (Figure 7). Cavitation may also result from nod- ular attenuation of bronchi or progressive primary disease, with the development of mul- tiple bilateral cavities in younger children who are usually very ill . The chest Figure 6. Consolidation and miliary TB. Frontal AP and lateral chest radiographs in a 3-year-old boy with con\ufb01rmed disseminated TB. This child did not receive BCG vaccination. ( a) Frontal AP and (b) lateral chest radiographs demonstrating right upper lobe consolidation with air bronchograms (black arrow) limited by the horizontal \ufb01ssure (white arrows), as well as parenchymal miliary TB nodules. The ability to identify peripheral consolidation with ultrasound is comparable to chest radiographs . This is consistent with previous pneumonia studies . Small consolidation (<0.5 cm), usually not identi\ufb01ed on chest radiographs, is more frequently seen when using ultrasound . Children over 5 years more commonly exhibit \u201ctree-in-bud\u201d consolidation on CT scan. This represents multiple areas of centrilobular nodules . As the disease progresses, consolidation may develop areas of caseous necrosis centrally\u2014this is represented by areas of low attenuation which do not enhance post-administration of contrast. Rarely, airspace disease progresses to cavity formation, as is commonly seen in adult TB . MRI is superior to CT in the characterization of tuberculous consolidation in that the MRI signal varies with the stage of necrosis and the presence of mycobacterium within the necrosis . Caseous necrosis in TB consolidation demonstrates a characteristic low signal on T2-weighted sequences and is an indicator of active TB [Figure 4].", "Pathogens 2022, 11, 161 10 of 15 4.3. Miliary TB Miliary TB is more common in young or immunocompromised patients occurring secondary to hematogenous spread of the disease. It is characterized on the chest radio- graph by the diffusion of small (<2 mm) non-calci\ufb01ed nodules, representing granulomas, appearing throughout the lung parenchyma, frequently in combination with thickened interlobular septal lines (Figure 6). However, in 25\u201340% of cases, chest radiographs are normal . Miliary nodules occur on CT well before they become visible on chest radiographs . 5. Post Primary TB Cavitation Post-primary cavitation is seen more commonly in adolescents and is the hallmark of post-primary TB on chest radiographs (Figure 7). Cavitation may also result from nodular attenuation of bronchi or progressive primary disease, with the development of multiple bilateral cavities in younger children who are usually very ill . The chest radiograph in the latter typically demonstrates air space consolidation and cavitation (resulting from caseous necrosis and liquefaction) in the upper lobes, and apical segments of the lower lobes. Air-\ufb02uid levels, usually resulting from secondary infection, may occur. These may be associated with multiple micronodules within a lobe or segment, representing post-primary bronchogenic spread . Pathogens 2022, 11, x FOR PEER REVIEW 11 of 16 radiograph in the latter typically demonstrates air space consolidation and cavitation (re- sulting from caseous necrosis and liquefaction) in the upper lobes, and apical segments of the lower lobes. Air -fluid levels, usually resulting from secondary infection, may occur. These may be associated with multiple micronodules within a lobe or segment, represent- ing post-primary bronchogenic spread . CT is not only superior in differentiating consolidation from cavitation, when com- pared with chest radiography, but it provides the ability to describe the cavity wall mor- phology . MRI is as sensitive as CT in the detection of cavities . Figure 7. Frontal PA chest radiograph in a 3 -year-old boy with confirmed pulmonary TB demon- strating right middle zone consolidation and cavitation (straight black arrow) containing an air - fluid level, as well as narrowing of the bronchus intermedius (curved black arrow). 6. Complications 6.1. Bronchiectasis Parenchymal destruction and chronic fibrosis can lead to traction bronchiectasis . Changes on chest radiograph may be subtle. Grossly dilated bronchial lumens and thick- ened bronchial walls lead to increased bronchovascular markings and bronchi -imaged end ons appear as ring shadows. CT is much more sensitive for demonstrating bronchiectasis.", "The \u2018tram track sign\u2019 represents thickened non -tapering bronchi. An increased broncho -arterial ratio, >0.8 in children , is indicative of bronchiectasis. When cut in a cross-section, the dilated bron- chi and smaller adjacent artery form the classic \u2018signet ring\u2019 sign. 6.2. Pleural Disease Pleural disease occurs via either of two mechanisms: direct spread f rom a caseating sub-pleural focus (consolidation or lymph node) or via hematogenous spread . Pleural disease is more common in older children . A pleural effusion may occur secondary to an obstruction of lymphatic drainage or as a result of a hyperse nsitivity reaction. This explains why most pleural fluid cultures are negative . They are typically unilateral, Figure 7. Frontal PA chest radiograph in a 3-year-old boy with con\ufb01rmed pulmonary TB demonstrat- ing right middle zone consolidation and cavitation (straight black arrow) containing an air-\ufb02uid level, as well as narrowing of the bronchus intermedius (curved black arrow). CT is not only superior in differentiating consolidation from cavitation, when com- pared with chest radiography, but it provides the ability to describe the cavity wall mor- phology . MRI is as sensitive as CT in the detection of cavities .", "Pathogens 2022, 11, 161 11 of 15 6. Complications 6.1. Bronchiectasis Parenchymal destruction and chronic \ufb01brosis can lead to traction bronchiectasis . Changes on chest radiograph may be subtle. Grossly dilated bronchial lumens and thick- ened bronchial walls lead to increased bronchovascular markings and bronchi-imaged end ons appear as ring shadows. CT is much more sensitive for demonstrating bronchiectasis. The \u2018tram track sign\u2019 represents thickened non-tapering bronchi. An increased broncho-arterial ratio, >0.8 in children , is indicative of bronchiectasis. When cut in a cross-section, the dilated bronchi and smaller adjacent artery form the classic \u2018signet ring\u2019 sign . 6.2. Pleural Disease Pleural disease occurs via either of two mechanisms: direct spread from a caseating sub-pleural focus (consolidation or lymph node) or via hematogenous spread . Pleural disease is more common in older children . A pleural effusion may occur secondary to an obstruction of lymphatic drainage or as a result of a hypersensitivity reaction. This explains why most pleural \ufb02uid cultures are negative . They are typically unilateral, lamellar (a linear density extending along the lateral chest wall and sparing the costophrenic angle), and associated with consolidation or lymphadenopathy (Figure 8). A large volume of pleural \ufb02uid needs to collect before becoming visible on plain \ufb01lms . Pathogens 2022, 11, x FOR PEER REVIEW 12 of 16 lamellar (a linear density extending along the lateral chest wall and sparing the costophrenic angle), and associated with consolidation or lymphadenopathy (Figure 8). A large volume of pleural fluid needs to collect before becoming visible on plain films . (a) (b) Figure 8. (a,b): (a) Supine AP chest radiograph in a 17 -month-old male with PTB demonstrating right sided pleural effusion with veiling of the right hemi-thorax and a lamellar component tracking up along the lateral chest wall (curved white arrows). There is also attenuation of the bronchi bilat- erally (straight black arrows), bowing of the trachea from lymphadenopathy (curved black arrow) and an enlarged, globular-shaped heart, consistent with a pericardial effusion (confirmed on ultra- sound, not shown here). ( b) Chest ultrasound confirming the pleural effusion (star) seen as hy- poechoic fluid between the parietal pleura, diaphragm, and right lung. A simple pleural effusion on ultrasound is characterized by an anechoic fluid collec- tion separating the visceral and parietal pleura. Ultrasound has been shown to be more sensitive than a chest radiograph for the presence of a tuberculous pleural effusion . An", "added benefit of ultrasound is the ability to further characterize the effusion by detect- ing the presence of loculations or empyema as well as guide drainage of these effusions if needed. CT and MRI have the ability to quantify the size of a pleural effusion and differentiate pleural thickening from an effusion. MRI is more sensitive than non-contrast CT for pleu- ral abnormalities , and MRI can better delineate internal debris and septations in pleural effusions . The \u2018split pleura\u2019 sign on CT\u2014linear smooth enhancing visceral and parietal pleura encasing a loculated collection \u2014represents empyema . Empyema is a non -specific finding most commonly occurring secondary to bacterial pneumonia; however, M. tuber- culosis remains an important cause in high-burden regions . Empyema can be compli- cated by fistula formation into the subcutaneous space or the bronchopulmonary tree . 6.3. Pericardial Disease TB pericarditis occurs due to the erosion of lymph nodes into the pericardium but may also occur due to hematogenous dissemination. Chest radiograph typically demon- strates an enlarged and globular cardiac silhouette . In pericardial disease, a CT scan will demonstrate pericardial thickening, with or without an effusion, as well as regional Figure 8. (a,b): (a) Supine AP chest radiograph in a 17-month-old male with PTB demonstrating right sided pleural effusion with veiling of the right hemi-thorax and a lamellar component tracking up along the lateral chest wall (curved white arrows). There is also attenuation of the bronchi bilaterally (straight black arrows), bowing of the trachea from lymphadenopathy (curved black arrow) and an enlarged, globular-shaped heart, consistent with a pericardial effusion (con\ufb01rmed on ultrasound, not shown here). (b) Chest ultrasound con\ufb01rming the pleural effusion (star) seen as hypoechoic \ufb02uid between the parietal pleura, diaphragm, and right lung. A simple pleural effusion on ultrasound is characterized by an anechoic \ufb02uid collection separating the visceral and parietal pleura. Ultrasound has been shown to be more sensitive than a chest radiograph for the presence of a tuberculous pleural effusion . An added bene\ufb01t of ultrasound is the ability to further characterize the effusion by detecting the presence of loculations or empyema as well as guide drainage of these effusions if needed.", "Pathogens 2022, 11, 161 12 of 15 CT and MRI have the ability to quantify the size of a pleural effusion and differentiate pleural thickening from an effusion. MRI is more sensitive than non-contrast CT for pleural abnormalities , and MRI can better delineate internal debris and septations in pleural effusions . The \u2018split pleura\u2019 sign on CT\u2014linear smooth enhancing visceral and parietal pleura encasing a loculated collection\u2014represents empyema . Empyema is a non-speci\ufb01c \ufb01nd- ing most commonly occurring secondary to bacterial pneumonia; however, M. tuberculosis remains an important cause in high-burden regions . Empyema can be complicated by \ufb01stula formation into the subcutaneous space or the bronchopulmonary tree . 6.3. Pericardial Disease TB pericarditis occurs due to the erosion of lymph nodes into the pericardium but may also occur due to hematogenous dissemination. Chest radiograph typically demon- strates an enlarged and globular cardiac silhouette . In pericardial disease, a CT scan will demonstrate pericardial thickening, with or without an effusion, as well as regional lymphadenopathy. The pericardial sac may be \ufb01brosed or calci\ufb01ed, which can result in constrictive pericarditis. 7. New Imaging Techniques/Technology Dynamic 4-D CT scans allow for 3D volumetric rendering of the airways for accurate measurement of bronchial stenosis length and could provide a safer non-invasive alterna- tive to bronchoscopy to assess tracheobronchomalacia (Table 3) . The anatomic detail provided by CT can help to determine the underlying cause for the stenosis and ultimately guide intervention . However, CT scanners with volume scanning capabilities are not widely available and the (unfounded) perception that they impart a higher radiation dose than bronchography limits its use . Table 3. Advantages and disadvantages of future imaging modalities. Imaging Modality Advantages Disadvantages Dynamic 4-D CT scans Accurately demonstrates tracheobronchomalacia. Demonstrates structures adjacent to the tracheobronchial tree. Non-invasive. Fast. Allows for 3D reconstruction. Limited availability. Perceived to impart a higher radiation dose than bronchography. Newer MRI techniques Provide ventilation and perfusion images in a single acquisition. Shorter acquisition times. No radiation exposure. High cost. Limited availability. Positron emission tomography (PET)/CT Highly sensitive in active TB. Reliably differentiates between active and latent disease. Assists with assessing response to treatment. Limited availability. Low speci\ufb01city with solitary pulmonary nodules. Computer aided detection software (CAD) Acceptable sensitivity (90%) and speci\ufb01city (70%) of a TB triage test. Cost-effective. User friendly. No human expertise needed to interpret Sparse literature regarding performance in paediatrics. Lower sensitivities in older patients", "Pathogens 2022, 11, 161 13 of 15 Newer MRI techniques can provide information regarding lung perfusion and venti- lation . High cost of hyperpolarized gas and dedicated hardware for lung ventilation MRI poses a challenge . Fourier decomposition is a new experimental technique that can provide ventilation and perfusion images in a single acquisition, and recent tests have provided information on hyperpolarized gas MRI and contrast-enhanced MRI . Priftakis et al. demonstrated that positron emission tomography (PET)/CT with 18F-\ufb02uorodeoxyglucose (FDG) is highly sensitive in active TB and has shown potential in the early detection of TB as well as in the assessment of the response to treatment . However, PET/CT with FDG has been shown to have a low speci\ufb01city in the setting of solitary pulmonary nodules with a poor ability to differentiate TB from malignancy. Availability is also limited. In the last two decades, computer-aided detection (CAD) software has been developed to independently locate and de\ufb01ne radiological abnormalities on chest radiographs and improve the sensitivity and speci\ufb01city, by predicting the likelihood of TB disease based on scoring systems . This software has been intended primarily for high-burdened, low-middle income countries with limited access to radiologists. It has been shown to be cost-effective and user friendly . In March 2020, the WHO endorsed the use of CAD software as an alternative to human interpretation of chest radiographs in TB screening and triage amongst susceptible adults, over the age of 15 years, after three commercially available software met WHO criteria for the minimal acceptable sensitivity (90%) and speci\ufb01city (70%) of a TB triage test, when compared with GeneXpert or culture . More recently, \ufb01ve commercially available arti\ufb01cial intelligence programs were anal- ysed using chest radiographs from 23,954 adults from Bangladesh presenting for TB screen- ing. All \ufb01ve algorithms were shown to signi\ufb01cantly outperform experienced radiologists in detecting abnormalities associated with PTB, with sensitivities above 90%. Furthermore, they resulted in a 50% reduction in the need for GeneXpert testing . Sensitivities varied between patient populations and contexts, with lower values in participants who were older, and those who had previous TB . Despite these promising data in adults, the literature regarding the performance of CAD in diagnosing primary TB and its complications in children is sparse, and further research is required . 8. Conclusions Chest imaging plays a crucial role in the diagnosis and management of pediatric PTB. Chest radiography remains the", "primary investigation for the assessment of PTB, especially in high burden areas. However, for lymphadenopathy, the cardinal sign of primary disease, chest radiography has low sensitivity and speci\ufb01city. The use of ultrasound, CT, or MRI can augment diagnostic ability, which can improve case detection. Newer imaging techniques such as dynamic 4D CT, (PET)/CT, and CAD software may improve radiological accuracy and help guide intervention. Author Contributions: Onceptualization and original draft\u2014M.N., Z.F.-S. and H.J.Z.; writing, review and editing\u2014M.N., Z.F.-S., T.P ., S.A. and H.J.Z. Images: S.A., M.N., Z.F.-S. and T.P . All authors have read and agreed to the published version of the manuscript. Funding: Supported by the Regional Prospective Observational Research in Tuberculosis (RePORT TB) Consortium, which is co-funded by the Medical Research Council (MRC) of South Africa and the US Of\ufb01ce of Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health USA (grant number DAA2\u201316\u201362066\u20131) and a South Africa -MRC grant to the Child & Adolescent Health Unit. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Con\ufb02icts of Interest: The authors declare no con\ufb02ict of interest.", "Pathogens 2022, 11, 161 14 of 15 References 1. 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J. 2021, 58, 2002990. [CrossRef] 35. Zampoli, M.; Kappos, A.; Wolter, N.; von Gottberg, A.; Verwey, C.; Mamathuba, R.; Zar, H.J. Etiology and incidence of pleural empyema in South African children. Pediatr. Infect. Dis. J. 2015, 34, 1305\u20131310. [CrossRef] 36. World Health Organization. WHO Rapid Communication WHO Rapid Communication on Systematic Screening for Tuberculosis. 2020. Available online: https://www.who.int/publications/i/item/rapid-communication-on-the-systematic-screening-for- tuberculosis (accessed on 26 August 2021). 37. Qin, Z.; Ahmed, S.; Sarker, M.S.; Paul, K.; Adel, A.S.S.; Naheyan, T.; Barrett, R.; Banu, S.; Creswell, J. Application of arti\ufb01cial intelligence in digital chest radiography reading for pulmonary tuberculosis screening. Lancet Digit. Health 2021, 3, 543\u2013554. [CrossRef] 38. Murphy, K.; Habib, S.S.; Zaidi, S.M.A.; Khowaja, S.; Khan, A.; Melendez, J.; Scholten, E.T.; Amad, F.; Schalekamp, S.; Verhagen, M.; et al. Computer aided detection of tuberculosis on chest radiographs: An evaluation of the CAD4TB v6", "\u00a9 World Health Organization 2016 All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications \u2013 whether for sale or for non-commercial distribution \u2013 should be addressed to WHO Press through the WHO website (http://www.who.int/about/licensing/copyright_form). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers\u2019 products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Cover photo: Knut L\u00f6nnroth, 2012. Printed in Switzerland. WHO/HTM/TB/2016.20 WHO Library Cataloguing-in-Publication Data Chest radiography in tuberculosis detection \u2013 summary of current WHO recommendations and guidance on programmatic approaches. I. World Health Organization. ISBN 978 92 4 151150 6 Subject headings are available from WHO institutional repository", "1 Chest radiography in tuberculosis detection T able of Contents Preface 2 Development process 3 Acknowledgements 4 Declarations of interests 4 Abbreviations 5 Definitions 5 1. INTRODUCTION 6 1.1 Medical imaging 6 1.2 Radiography 6 1.3 Chest X -ray for detecting TB 6 1.4 Overview of the use of chest X -ray in WHO\u2019s policies and guidelines 7 2. CHEST X -RAY AS A TRIAGE TOOL 10 2.1 Definition of triaging 10 2.2 T riaging for TB among people with respiratory complaints 10 2.3 TB triage algorithm options 12 3. CHEST X -RAY AS A DIAGNOSTIC AID 17 3.1 Chest X -ray as a diagnostic aid for respiratory and other intrathoracic diseases 17 3.2 Chest X -ray as a complement to bacteriological TB tests 17 3.3 Chest X -ray as part of a comprehensive diagnostic pathway in children 18 4. CHEST X -RAY AS A SCREENING TOOL FOR PULMONARY TB 20 4.1 Chest X -ray as a sensitive tool for screening for active TB 20 4.2 Chest X -ray screening in TB prevalence surveys 22 4.3 Chest X -ray to rule out active TB before treating latent infection 24 5. TECHNICAL SPECIFICA TION, QUALITY ASSURANCE, QUALITY CONTROL, AND SAFETY 25 5.1 T echnologies for chest X-ray and technical specifications 25 5.2 How to choose chest X -ray technology 26 5.3 Computer -aided detection of TB 26 5.4 Quality assurance and quality control 28 5.5 Safety 29 6. STRA TEGIC PLANNING FOR USING CHEST X-RAY IN NATIONAL TB CARE 31 Annexes 34 Annex 1. Yield and costs of triage algorithms in a hypothetical population of 100 000 with different TB prevalence levels 34 Annex 2. Proportion of TB cases detectable through screening with chest X-ray or by screening for chronic cough 37 References 38", "2 Chest radiography in tuberculosis detection Preface The End TB Strategy puts renewed emphasis on the need to ensure early and correct diagnosis for all people with tuberculosis (TB) (1). Important progress has been made in improving laboratory services in recent decades. New bacteriological tests for TB diagnosis have become available and their use is now being scaled up (2, 3). Efforts have been made to ensure that people who seek care and have symptoms consistent with TB are correctly triaged and evaluated for TB. Systematic screening for active TB in high- risk groups is being implemented and scaled up in several places (4, 5). However, despite these efforts, many people with TB remain undiagnosed or are diagnosed only after long delays (6). Chest radiography, or chest X-ray (CXR), is an important tool for triaging and screening for pulmonary TB, and it is also useful to aid diagnosis when pulmonary TB cannot be confirmed bacteriologically. Although recent diagnostic strategies have given specific prominence to bacteriology, CXR can be used for selecting individuals for referral for bacteriological examination, and the role of radiology remains important when bacteriological tests cannot provide a clear answer. Access to high-quality radiography is limited in many settings. Ensuring the wider and quality-assured use of CXR for TB detection in combination with laboratory- based diagnostic tests recommended by the World Health Organization (WHO), can contribute to earlier TB diagnosis and potentially to closing the TB case-detection gap when used as part of algorithms within a framework of health-system and laboratory strengthening. This document summarizes WHO\u2019s recommendations on using CXR for TB triaging, diagnosis and screening. It also outlines a framework for the strategic planning and use of CXR within national TB programmes (NTP). Moreover, the document provides a brief overview of technical specifications, and quality assurance and safety considerations for CXR. However, because these technical aspects are generic and should be addressed as part of the general strengthening of radiography and imaging services, this document does not go into technical details. General radiography guidance is provided elsewhere (7-11). The document focuses on CXR, with a major emphasis on detecting pulmonary TB. CXR can be useful for diagnosing other forms of TB (for example, miliary or pericardial TB, or tuberculous effusions) and other imaging techniques are also valuable for TB diagnosis, for example, for extrapulmonary TB, but these topics are not discussed in this document. The document is", "3 Chest radiography in tuberculosis detection Development process A steering group was established in January 2016, which advised WHO on the scope and content of this document. The members of the steering group were Faiz Ahmad Khan, Sevim Ahmedov, Frank Cobelens, Jacob Creswell, Claudia Denkinger, Christopher Gilpin, Michael Kimerling, Knut L\u00f6nnroth, Cecily Miller, YaDiul Mukadi, Ikushi Onozaki and Madhukar Pai. After consultation with WHO\u2019s Guideline Review Committee, it was determined that the document is not a new guideline but a summary of existing WHO recommendations. Therefore, it did not need to follow WHO\u2019s guideline development process. All major WHO publications about TB were reviewed for their relevance to the use of CXR in screening for, triaging and diagnosing TB. Recommendations across all documents were compiled and summarized. An accompanying framework for strategic planning for using CXR within NTPS was developed based on experts\u2019 opinions. No systematic literature review was undertaken during the development of this document. The evidence base for the statements made in this document is the same as for those in the cited WHO guidelines and policy frameworks. Scenarios for the yield of TB (true positive/true negative and false positive/false negative) for different triaging algorithms were modelled using the ScreenTB tool (12) to illustrate how the different placement of CXR in an algorithm influences yields and costs under different epidemiological scenarios. The model outputs that are included in this document should not be used for forecasting TB detection, but are included merely to demonstrate how variations in algorithms influence TB detection and costs. Readers are advised to develop setting-specific scenarios based on the local TB epidemiology and the best data about test accuracy and costs. A first draft was completed in July 2016 and was circulated to experts (see below) for peer review. Based on comments from the peer review, a second draft was prepared ahead of a global consultation held during 28\u201329 September 2016. The consultation provided additional inputs on the draft document, and the documented was thereafter finalized.", "4 Chest radiography in tuberculosis detection Acknowledgements The first draft was prepared by Cecily Miller and Knut L\u00f6nnroth. The following persons contributed to the development of the document or peer reviewed it, or both: Faiz Ahmad Khan, Sevim Ahmedov, Farhana Amanullah, Samiha Baghdadi, Draurio Barreira, Adriana Velazquez Berumen, Nils Billo, Annemieke Brands, Grania Brigden, Chen-Yuan Chiang, Maarten van Cleeff, Jacob Creswell, Claudia Denkinger, Anna-Marie Celina Garfin, Nebiat Gebreselassie, Sifrash Meseret Gelaw, Wayne van Gemert, Robert Gie, Steve Graham, Rob van Hest, Philip Hopewell, Bogomil Kohlbrenner, Alexei Korobitsyn, Devesh Gupta, Michael Kimerling, Irwin Law, Partha Pratim Mandal, Guy Marks, Giovanni Batista Migliori, Mahshid Nasehi, Nobuyuki Nishikiori, Pierre-Yves Norval, Kosuke Okada, Ikushi Onozaki, Salah-Eddine Ottmani, Madhukar Pai, Tripti Pande, Mario Raviglione, Maria del Rosario P\u00e9rez, Anna Scardigli, Eric Stern, Beat Stoll, Etienne- Leroy T erquem, Belay T essema, Mukund Uplekar, Diana Weil, William Wells, Marieke van der Werf and Christine Whalen. Declarations of interests The following interests were declared by the experts consulted. Declared interests that were deemed not significant \u2022 Claudia Denkinger: took part in several clinical research projects to evaluate new diagnostic tests against the target product profiles for TB defined through consensus processes led by WHO. These studies were for diagnostic products developed by private sector companies (Cepheid, Epistem, Molbio Diagnostics, Hain Lifescience, Nipro, Becton Dickinson, Alere, YD Diagnostics, Ustar Biotechnologies and Qiagen) that provide access to know-how, equipment and reagents, and contribute through unrestricted donations as per FIND (Foundation for Innovative New Diagnostics) policy. \u2022 Bogomil K ohlbrenner and Beat Stoll: were employed as researchers on a project to develop appropriate medical devices and appropriate training for health workers in the field of tropical medical imaging; it was a philanthropic project. Declared interest that were deemed significant for making recommendations to WHO about whether to develop guidelines for computer-aided detection \u2022 F aiz Ahmad Khan and Madhukar Pai: received a research grant to study the diagnostic accuracy of CAD4TB (developed by Delft Imaging Systems, Veenendaal, the Netherlands) in collaboration with Interactive Research & Development, who have purchased equipment from the makers of CAD4TB. The developers of CAD4TB are not collaborators or in any way involved in the research. Faiz Ahmad Khan and Madhukar Pai were invited to present the systematic review on CAD for TB detection, provide comments throughout the meeting, and peer-review draft documents. However, they were not part of the decision to advise WHO on the", "5 Chest radiography in tuberculosis detection Abbreviations AFB acid-fast bacilli CAD computer -aided detection CXR chest X -ray or chest radiography HIV human immunodeficiency virus L TBI latent tuberculosis infection MTB Mycobacterium tuberculosis NTP national tuberculosis programme PICO population, intervention, comparator , outcome QUADAS Quality Assessment of Diagnostic Accuracy Studies S SM sputum-smear microscopy TB tuberculosis WHO W orld Health Organization Definitions Bacteriologically confirmed TB case: A bacteriologically confirmed case of TB is one from whom a biological specimen tests positive by smear microscopy, culture or WHO-recommended rapid diagnostic (such as the Xpert MTB/RIF assay). All such cases should be notified, regardless of whether TB treatment has started (13). Clinically diagnosed TB case: A clinically diagnosed case of TB is one who does not fulfil the criteria for bacteriological confirmation but has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give the patient a full course of anti-TB treatment. This definition includes cases diagnosed on the basis of abnormalities seen on X-ray or histology suggestive of TB, and extrapulmonary cases without laboratory confirmation. Clinically diagnosed cases subsequently found to be bacteriologically positive (before or after starting treatment) should be reclassified as bacteriologically confirmed (13). Systematic screening for active TB: is the systematic identification of people with suspected active TB in a predetermined target group, using tests, examinations or other procedures that can be applied rapidly (4). Unlike evaluations of those who actively seek care for respiratory symptoms (known as triaging), the systematic screening of individuals for TB is typically initiated by a provider and offered in a systematic way to an apparently healthy target group that has been determined to have a high risk of TB. Triaging: For the purpose of this document, triaging is defined as the processes of deciding the diagnostic and care pathways for people seeking healthcare, based on their symptoms, signs, risk markers and test results. Triaging involves assessing the likelihood of various differential diagnoses as a basis for making clinical decisions. It can follow more- or less-standardized protocols and algorithms and may be done in multiple steps.", "6 Chest radiography in tuberculosis detection 1. INTRODUCTION 1.1 Medical imaging Medical imaging uses different modalities and processes to image the internal structures of the human body for diagnosis and treatment. Imaging has an important role in healthcare for all population groups. In public health and preventive medicine, as well as in both curative and palliative care, effective clinical decisions depend on correctly screening, triaging and diagnosing patients. The use of imaging services is paramount in correctly screening, confirming and documenting the course of many diseases. With the improved availability of medical equipment, global access to medical imaging has increased considerably, but is still insufficient in many settings (14). Medical imaging is a key element within many evidence-based clinical decision-support algorithms, consistent with overarching evidence-based recommendations for disease management (14). As such, medical imaging should be accessible to all and should not be exclusively a hospital service (15). 1.2 Radiography Radiography uses X-rays to visualize the internal structures of a patient. X-rays are a form of electromagnetic radiation produced by an X-ray tube. The X-rays pass through the body and are captured behind the patient by film that is sensitive to X-rays or by a digital detector. Different tissues in the body vary in their absorption of X-rays: dense bone absorbs more radiation, but soft tissue allows more to pass through. This variance produces contrasts within the image to give a two-dimensional representation of the three-dimensional structures. As a result, the X-ray image often includes overlapping structures. A thorough knowledge of anatomy is needed to identify an abnormality on an X-ray and understand where it is in the body. Common clinical applications include imaging the chest to assess lung and intrathoracic pathologies; imaging the skeletal system to examine bone structures and diagnose fractures, dislocations or other bone pathologies; imaging the abdomen to assess obstructions or free air or fluid within the abdominal cavity; or imaging the teeth to assess common dental pathologies, such as cavities or abscesses (14). 1.3 Chest X-ray for detecting TB Chest X-ray (CXR) is a rapid imaging technique that allows lung abnormalities to be identified. CXR is used to diagnose conditions of the thoracic cavity, including the airways, ribs, lungs, heart and diaphragm. CXR has historically been one of the primary tools for detecting tuberculosis (TB), especially pulmonary TB. CXR has high sensitivity for pulmonary TB and thus is a valuable tool to identify TB as", "a differential diagnosis for patients, especially when the X-ray is read to identify any abnormality that is consistent with TB. However, CXR has poor specificity; although some CXR abnormalities are rather specific for pulmonary TB (for example, cavities), many CXR abnormalities that are consistent with pulmonary TB are seen also in several other lung pathologies and, therefore, are indicative not only of TB but also of other pathologies. Moreover, there is significant intra- and interobserver variation in the reading of CXRs. Relying only on CXR for TB diagnosis leads to overdiagnosis, as well as underdiagnosis (16). Rigorous efforts should always be made to base a TB diagnosis on bacteriological confirmation (sputum-smear microscopy, culture or a molecular test). WHO classifies TB diagnosis into bacteriologically confirmed TB, if it is based on bacteriological confirmation, or clinically diagnosed TB, if it is based on clinical assessment including CXR, but is not confirmed by bacteriological examination (13).", "7 Chest radiography in tuberculosis detection 1.4 Overview of the use of chest X-ray in WHO\u2019s policies and guidelines For many years, WHO has recommended CXR as a diagnostic tool to be used as a complementary part of the clinical diagnosis of bacteriologically negative TB. As such, CXR has previously been placed at the end of diagnostic algorithms. WHO\u2019s 2003 treatment guidelines for national programmes and the guideline on diagnosing smear-negative pulmonary TB from 2007 recommended that CXR be used after: (i) initial negative bacteriological testing, (ii) a course of broad-spectrum antibiotics and (iii) a second negative round of bacteriological testing (17, 18). However, CXR was recommended to be used directly after initial negative bacteriological testing to diagnose TB in people living with HIV or AIDS and in those considered to be at high risk of HIV infection(18). The 2008 handbook for national tuberculosis control programmes (19), as well as the third edition of the International standards for tuberculosis care in 2014 (20), suggested a more flexible approach, with the possibility of using CXR directly after an initial negative bacteriological test, and not just for people living with HIV . None of these guidelines placed CXR as a triage test before bacteriological testing. However, none of the guidelines specifically recommend against using CXR for triaging or diagnostic evaluation of TB, and they emphasized that whenever CXR has been done and shows abnormalities consistent with TB, a bacteriological test for TB must always be performed. All the above-mentioned documents emphasized that using CXR to diagnose TB is problematic, given that CXR has low specificity and significant interobserver variation. Moreover, poor access to high-quality radiography equipment and expert interpretation, along with the widespread use of low-quality radiography, were identified as additional barriers for promoting large-scale programmatic use. Recently, however, CXR has been promoted as a useful tool that can be placed early in screening and triaging algorithms. An important reason for rethinking the role of CXR in screening and diagnostic algorithms is that numerous national TB prevalence surveys have demonstrated that CXR is the most sensitive screening tool for pulmonary TB and that a significant proportion of people with TB are asymptomatic, at least early in the course of the disease (see Annex 2) (21). Other factors that have contributed to CXR becoming an increasingly accepted part of programmatic approaches to TB care and prevention include: \u2022 the increased availability of radiography,", "including digital radiography with its lower running costs and highly portable systems for field use, better image quality and better safety (due to decreased radiation dose) than conventional radiography, as well as possibilities for use for telemedicine; \u2022 the documented rapidity of results and high throughput capacity , especially of digital CXR; \u2022 a gradual shift from strictly prioritizing the diagnosis of the most infectious TB cases (that is, bacteriologically confirmed TB, especially sputum smear-positive TB, in persons with persistent cough) to programmatic targets in line with a rights-based vision of universal access to high-quality diagnosis for all people with all forms of TB as well as concern with diagnosis of other lung diseases; \u2022 the increasing availability of rapid molecular tests with higher sensitivity and specificity than sputum- smear microscopy which allows for higher diagnostic accuracy among people with CXR abnormalities consistent with TB (and, thus, reduces the risk of overdiagnosis). Moreover , available molecular tests have significantly higher costs than sputum smear microscopy, which often necessitates a method of triaging of patients for evaluation for TB.", "8 Chest radiography in tuberculosis detection The limitations of, and recent advances in, CXR are summarized in Box 1. BOX 1. Limitations of and advances in chest X-ray (21) The main limitations associated with using chest X-ray include: \u2022 it produces two-dimensional representations of a three-dimensional structure; \u2022 there is intrareader and interreader variability; \u2022 no abnormalities are definitive of TB, therefore the specificity is low; \u2022 a universally accepted reporting system is lacking; \u2022 patients are exposed to ionizing radiation; \u2022 special equipment (with adequate input power) is needed; \u2022 trained personnel are required to operate the machine and interpret the results; \u2022 there is often limited access in rural areas; access is often limited to district or regional levels; \u2022 there is limited archiving of hard copies; \u2022 out-of -pocket costs for patients are often high. Recent advances in digital chest X-ray technology include: \u2022 lower operating costs; \u2022 improved and more reproducible image quality with enlargement capability; \u2022 a decreased radiation dose; \u2022 improved portable systems that can be used for mobile units; \u2022 efforts to harmonize interpretation and reporting; \u2022 the potential of objective tools for interpretation of digital images, such as computer -aided detection; \u2022 better (digital) archiving facilities; \u2022 film processing equipment and hard copies no longer required; \u2022 the possibility of electronically transmitting images (for example, for telemedicine or quality assurance). The importance of CXR is reflected by the recommendations about using CXR for screening, triaging and assisting in the diagnosis of TB that have been included in recent policies developed or endorsed by WHO , including: \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Guidance for national tuberculosis programmes on the management of tuberculosis in children (22) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 the implementation manual for the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA , United States) (3) \u2022 International standards for tuberculosis care, third edition (20) \u2022 Guidelines on the management of latent tuberculosis infection (24). Box 2 summarizes the recent recommendations from WHO. However, despite the demonstrated utility of CXR and multiple WHO recommendations about when and how to use it, the programmatic and rational use of CXR for TB detection remains limited. The lack of consolidated programmatic guidance is one possible reason, hence the need for this", "document. Also contributing to its restricted use are the limited availability of radiography in some regions (including a lack of systems and incentives to keep X-ray machines operational), constraints on human resources, insufficient training (including qualification programmes and post-graduate training), a lack of quality assurance programmes and, often, high out-of-pocket costs for patients. In the following chapters, the options for using CXR for different elements of TB detection are outlined in more detail. This is followed by a brief summary of technical specifications, and quality control and safety issues. Finally, guidance on the programmatic planning and implementation of CXR is discussed.", "9 Chest radiography in tuberculosis detection BOX 2. Summary of recommendations on using chest X-ray (CXR) for TB in recent WHO guidelines and policies CHEST X-RAY: AN ESSENTIAL TOOL TO END TB CXR IS A SENSITIVE TOOL FOR SCREENING FOR ACTIVE TB Reference: Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 CXR has higher sensitivity for pulmonary TB than screening for TB symptoms. AN ABNORMAL CXR IS AN INDICA TION FOR FULL DIAGNOSTIC EVALUATION Reference: International standards for tuberculosis care (20) \u2022 All patients with unexplained fi ndings suggestive of TB on CXR should be evaluated for TB with a bacteriological diagnostic test. \u2022 CXR can be used as a supplementary diagnostic aid, although the specificity is low . \u2022 A bacteriologically confirmed diagnosis is always preferred. CXR IS AN IMPORT ANT TOOL FOR DIAGNOSING CHILDHOOD TB Reference: Guidance for national tuberculosis programmes on the management of tuberculosis in children (22) \u2022 CXR is useful in diagnosing pulmonary and extrapulmonary TB in children in combination with history , evidence of TB infection and microbiological testing. CXR CAN IMPROVE THE EFFICIENCY OF USING THE XPERT MTB/RIF ASSAY Reference: implementation manual for the Xpert MTB/RIF assay (3) \u2022 CXR and further clinical assessment can be used to triage who should be tested with the Xpert MTB/RIF assay to reduce the number of individuals tested and the associat ed costs, as well as to improve the pre- test probability for TB and, thus, the predictive value of the Xpert MTB/RIF assay. CXR CAN ASSIST IN DIAGNOSING TB AMONG PEOPLE LIVING WITH HIV Reference: Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 CXR can assist in diagnosing TB among people living with HIV . It is particularly useful for ruling out TB disease before providing treatment for latent TB infection. CXR HELPS RULE OUT ACTIVE TB BEFORE TREATING LATENT TB INFECTION Reference: Guidelines on the management of latent tuberculosis infection (24) \u2022 CXR used in combination with symptom screening has the highest sensitivity for detecting TB and, thus, should be used to exclude active TB before initiating treatment o f latent TB infection. \u2022 Individuals with any radiological abnormality or TB symptoms should be investigated further for active TB and other conditions. CXR IS AN ES SENTIAL TECHNOLOGY FOR PREVALENCE SURVEYS Reference: Tuberculosis prevalence surveys: a handbook (21) \u2022 CXR is a necessary screening", "tool to identify survey participants eligible for bacteriological examination; in recent surveys, CXR has proven essential for detecting a large pr oportion of prevalent TB cases. More information can be found in the following resources: \u2022 WHO\u2019s diagnostic imaging website (14) \u2022 The WHO manual of diagnostic imaging: radiographic anatomy and interpretation of the chest and the pulmonary system (7) \u2022 International standards for tuberculosis care, third edition (20) - Standards for TB care in India (25) - European Union standards for tuberculosis care (26) - Canadian tuberculosis standards, seventh edition (27) \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Systematic screening for active tuberculosis: an operational guide (5) \u2022 Guidelines on the management of latent tuberculosis infection (24) \u2022 Guidance for national tuberculosis programmes on the management of tuberculosis in children, second edition (22) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 Xpert MTB/RIF implementation manual (3) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 P ocket book of hospital care for children (28) \u2022 the website for the Practical approach to Lung Health (known as P AL) (29).", "10 Chest radiography in tuberculosis detection 2. CHEST X-RAY AS A TRIAGE TOOL 2.1 Definition of triaging For the purpose of this document, triaging is defined as the processes of deciding the diagnostic and care pathways for people seeking healthcare, based on their symptoms, signs, risk markers and test results. Triaging involves assessing the likelihood of various differential diagnoses as a basis for making clinical decisions. It can follow more- or less-standardized protocols and algorithms and may be done in multiple steps. Effective triaging that helps to rapidly identify TB is important both for optimizing care for the individual and for ensuring good infection control (30). Triaging protocols should be adapted to the disease\u2019s epidemiology in a given setting because the prevalence of different diseases determines the predictive values of symptoms, signs, risk markers and test results. Triaging is different from systematic screening in that it focuses on the clinical management of a person seeking healthcare for one or several unexplained complaints or concerns, while systematic screening normally is initiated by a provider and targets apparently healthy individuals with or without risk markers for a given disease; for more information on systematic screening see Systematic screening for active tuberculosis: principles and recommendations (4) and the associated Systematic screening for active tuberculosis: an operational guide (5). 2.2 Triaging for TB among people with respiratory complaints Proper triaging of people seeking healthcare with respiratory complaints is essential for diagnosing TB correctly and early, as well as for the early diagnosis of other conditions. Unfortunately, not all people seeking care with symptoms consistent with TB receive an adequate evaluation for TB. These failures result in missed opportunities for detecting TB early and lead to increased disease severity, more complications and a higher risk of poor treatment outcomes for the patients. They also can lead to a greater overall disease burden in the community because they increase the likelihood of transmission of Mycobacterium tuberculosis in health facilities and to family members and others in the community. For this reason, effective and efficient clinical triaging algorithms are of utmost importance; for more information see the International standards for tuberculosis care (20). People with pulmonary TB who are seeking care often initially present with non-specific respiratory symptoms that need to be evaluated. Respiratory conditions are among the most common acute and chronic diseases worldwide; they occur in all societies and in all age groups. The heavy", "burden of respiratory diseases means that their symptoms are some of the most common reasons why patients seek primary healthcare: respiratory complaints (including cough, sputum production, and shortness of breath) often constitute around 20% of the symptoms that prompt a visit to a primary health centre (31); for more information see the website for the Practical approach to Lung Health (known as PAL) (29). Thus, respiratory symptoms are both common and non-specific. Most people with respiratory symptoms consistent with TB do not have TB, even in setting where TB is highly endemic. Therefore, it is important to identify in a sensitive and efficient manner those who have a high likelihood of TB among those with respiratory symptoms and to determine the underlying cause of disease for those who are not ultimately diagnosed with TB. Triage algorithms that are appropriate to specific patient populations, the epidemiology of respiratory conditions, and healthcare-system capacity are essential for providing high-quality care. Where it is available and feasible in the outpatient primary care setting, CXR can be used as an effective triage test for those seeking care for respiratory complaints. CXR is a sensitive tool for identifying TB, meaning that it identifies most people with a high likelihood of having the disease, while correctly ruling out TB in most persons when the X-ray is read to look for any abnormality consistent with TB. In addition, CXR can help identify other pulmonary conditions, such as lung cancer and occupational lung diseases like silicosis, as well as other intrathoracic diseases that require further diagnostic evaluation. Therefore, CXR is a useful general triage test for pulmonary conditions because it helps identify which type of further diagnostic evaluation patients require to correctly diagnose the cause of their illness. A normal CXR helps", "11 Chest radiography in tuberculosis detection rule out a number of pulmonary conditions and prompts diagnostic evaluation for conditions consistent with no radiological findings, while an abnormal CXR prompts evaluation for conditions consistent with radiographic changes, including but not limited to bacteriological evaluation for TB (Fig. 1). In any case, when used as a triage test, CXR should be followed by further diagnostic evaluation to establish a diagnosis. Generating differential diagnoses for conditions other than TB may be the primary objective of ordering a CXR. Regardless of the reason for obtaining a CXR, it is important that any CXR abnormality consistent with TB be further evaluated with a bacteriological test (20). FIG. 1. Using chest radiography as a triage tool AFB: acid-fast bacilli; CXR: chest X-ray; MTB: Mycobacterium tuberculosis, TB: tuberculosis. CXR may have higher specificity for pulmonary TB than assessing symptoms alone, depending on how the X-ray is read. Therefore, triaging using CXR can help reduce the number of persons who undergo bacteriological TB testing without decreasing the detection of true TB cases. CXR also improves the positive predictive value of subsequent bacteriological tests by increasing the pre-test probability of TB (4). Beyond identifying active TB disease, CXR also identifies one of the populations at highest risk of developing TB disease: those who have inactive TB or fibrotic lesions without a history of TB treatment. Once active TB has been excluded, patients with fibrotic lesions should be followed-up, given their high risk for developing active disease (4). There is no comprehensive WHO guidance on using CXR in triaging individuals with respiratory symptoms. In the absence of such guidance, this chapter presents options for approaches to triage, and the contribution of CXR to each approach is described. Indication for CXR Additional evaluation as indicated CXR Normal Consistent with TB Bacteriological evaluation of TB AFB or MTB present Abnormal Not consistent with TB AFB or MTB not present", "12 Chest radiography in tuberculosis detection 2.3 TB triage algorithm options In this section, different triage algorithms for patients with respiratory complaints are discussed (up to the point of ordering an initial bacteriological test for TB) and compared to help guide the choice of an appropriate algorithm for different situations. At the end of the section, the algorithms are displayed schematically, together with indications of the yield of true positives and false positives for TB and the cost per true TB case detected, based on modelled yields and costs in a hypothetical scenario in which the prevalence of TB is 0.5% (500 cases/100 000 population) among persons entering the triage algorithm (Fig. 2). Details and additional scenarios are provided in Annex 1. The estimated yield shown concerns only bacteriologically confirmed TB, and the yield of false-positive TB corresponds to a false positive only on initial bacteriological testing. Actions to be taken after a positive or negative initial bacteriological test \u2013 including further evaluation for TB, drug resistance and for other underlying conditions, as well as the yield of true-positive and false-positive TB based on clinical diagnosis \u2013 are discussed in Section 2.3.3. and Chapter 3. In line with the progressive realization of universal health coverage, out-of-pocket expenditures for CXR, as well as for bacteriological and other tests, should be minimized (32). Costs should be covered through fair third-party financing. If CXR is used for triaging and the subsequent diagnostic evaluation of patients with respiratory complaints, CXR and bacteriological tests should be free of charge for patients. The algorithm scenarios discussed here and displayed in Fig. 2 and in Annex 1 assume there are no direct costs for patients and estimate the potential magnitude of costs from a healthcare perspective of various approaches to triaging for TB, including using CXR and other tools. When tools are available only on the referral level, additional indirect costs for patients, as well as transport, feasibility and time factors, need to be considered when choosing an appropriate algorithm. Further discussion of CXR infrastructure, planning and financing can be found in Chapter 6. 2.3.1 Optimizing TB triaging when sputum-smear microscopy is used as bacteriological test Traditionally, chronic and productive cough (with a duration of longer than 2\u20133 weeks) has been used by national tuberculosis programmes (NTPs) as a triaging criterion for determining who should undergo sputum-smear microscopy (Algorithm 1). This approach identifies people with an advanced", "stage of TB, and it is a rational public health approach when the priority is to detect highly infectious pulmonary TB or when CXR is not available. If available, CXR can be used as an additional triage test after initially triaging for chronic cough (Algorithm 2). Because CXR is sensitive, Algorithm 2 has a similar yield to Algorithm 1 of true-positive cases detected with sputum-smear microscopy while reducing the number of persons who need to undergo sputum-smear microscopy. However, the cost can be higher, depending on the cost of CXR as compared with the cost of sputum-smear microscopy. The number of false-positive sputum- smear microscopy results is low for both of these algorithms when the TB prevalence is moderate to high, although it is lower in Algorithm 2, which includes CXR. However, introducing CXR before a bacteriological test can increase the total number of clinically diagnosed cases and, thus, also the total number of false- positive cases, depending on what further diagnostic evaluation and treatment decisions are made for patients with abnormal CXR and negative bacteriological tests (see Section 2.3.3. and Chapter 3). Triage algorithms based on chronic cough have a low sensitivity for TB, and, thus, many cases will be missed with this approach, especially in the early stages of disease. Recent TB prevalence surveys have demonstrated that a large proportion of people with bacteriologically confirmed TB do not experience chronic cough (21). Annex 2 shows the proportion detectable through screening with CXR and screening for chronic cough among persons with bacteriologically confirmed TB detected in recent TB prevalence surveys. Earlier and more complete detection of TB among people seeking healthcare may, therefore, require bacteriological testing for TB using broader indications, especially in TB-endemic settings. This may include testing all people with any symptom or sign consistent with TB (that is, any one of cough, haemoptysis, fever, night sweats or weight loss) as in Algorithm 3, or testing those with a predefined constellation of symptoms, signs and clinical or population-based risk markers for TB (for example, HIV , other immune- compromising conditions, diabetes, renal failure, smoking, alcohol or substance abuse, undernutrition, poverty, homelessness, history of imprisonment, migration from a TB-endemic setting). The appropriate threshold or indication for applying a bacteriological test depends on the local TB epidemiology. As a guiding principle, the higher the TB prevalence, the broader the indication for TB testing should be.", "13 Chest radiography in tuberculosis detection T esting using a broad indication, such as any symptom consistent with TB, increases the total yield of TB cases detected. However, it can lead to high demands on resources and overloaded laboratories. It also leads to a lower positive predictive value for the bacteriological test result and, thus, a higher risk of false-positive test results. Narrowing symptom criteria will, in most situations, lower the sensitivity while increasing the specificity, and reduce the number who need to undergo bacteriological testing. Using CXR as an additional triage test is especially useful in the context of more inclusive initial symptom triaging, and it can lead to a high total yield with fewer bacteriological tests per detected case and fewer false- positive sputum-smear microscopy results as compared with symptom screening alone (see Algorithm 4). However, introducing CXR into an algorithm that uses smear microscopy as the bacteriological test can increase the cost per true case detected, depending on the relative costs of CXR and microscopy. It can also increase the number of clinically diagnosed cases, of which a substantial proportion may be false positives if proper quality control of clinical diagnosis is not in place (see Section 2.3.3. and Chapter 3). Algorithm 5 uses CXR as an initial triage test (regardless of symptoms, signs and other risk markers), which has been suggested as a rigorous triaging approach for healthcare facilities in some hyperendemic settings). It improves the sensitivity of triaging as compared with initial symptom-based triaging and, thus, improves case detection, but it can increase resource demands considerably, including for laboratories. Such an approach is equivalent to systematic TB screening in health facilities, which is further discussed in Chapter 3. 2.3.2 Chest X-ray triaging to optimize use of the Xpert MTB/RIF assay As NTPs adopt and roll out the Xpert MTB/RIF assay into routine practice for TB diagnosis, it becomes important to determine how the test can be most efficiently used in evaluating patients with suspected TB; for more information see the Xpert MTB/RIF implementation manual (3). In Algorithm 6, replacing sputum-smear microscopy with the Xpert MTB/RIF assay as the primary bacteriological test after initial triaging for chronic cough increases the yield of bacteriologically confirmed TB. However, the cost per true case detected is considerably higher than with an algorithm using sputum- smear microscopy due to the higher costs for the Xpert MTB/RIF assay. One approach to", "reducing the number of individuals who undergo Xpert MTB/RIF testing without significantly reducing the yield of TB cases detected is to use Algorithm 7; in this algorithm CXR is used as a second triage test after initial triaging for chronic cough, after which patients with abnormal CXR results are referred for Xpert MTB/RIF testing for confirmatory diagnostic evaluation. If CXR is readily available and considerably cheaper than Xpert MTB/RIF testing, which is often the case, especially with digital CXR, this could greatly reduce the cost per true case detected. CXR triaging also increases the positive predictive value of Xpert MTB/RIF testing. The specificity of the Xpert MTB/RIF assay for detecting TB is high (99%, with liquid culture as reference standard) (2). However, given that it is not 100%, the positive predictive value of Xpert MTB/ RIF testing may be low when applied to groups with a relatively low TB prevalence. Using CXR as a triage test for those who have chronic cough and then referring those with abnormal results for confirmatory testing with the Xpert MTB/RIF assay results in a higher prevalence of TB in the group tested and, thus, increases the positive predictive value and minimizes false-positive results. Using CXR as a triage test is further discussed in the Xpert MTB/RIF implementation manual (3). However, the sensitivity of Algorithms 6 and 7 remains limited due to the low sensitivity of the initial triaging for chronic cough. In order for Xpert MTB/RIF testing to significantly improve early TB detection it may need to be used with a broad indication. Using Xpert MTB/RIF testing as the primary diagnostic test after triaging for any TB symptoms is a highly sensitive approach (see Algorithm 8). However, this algorithm is expensive and requires high-throughput capacity for Xpert MTB/RIF testing. Using CXR as a second triage test is especially valuable when the initial triaging is for any TB symptom (see Algorithm 9). Algorithm 9 can significantly reduce the laboratory burden, cost per true case detected and false-positive bacteriological test results. As discussed in Section 2.3.1, introducing CXR before a bacteriological test can increase the total number of clinically diagnosed cases and, thus, also the total number of false-positive cases, depending on what further evaluation and treatment decisions are made for patients with abnormal CXR and negative bacteriological tests. This is more likely when sputum-smear microscopy is used than when Xpert MTB/", "14 Chest radiography in tuberculosis detection RIF testing is used because the Xpert MTB/RIF assay is more sensitive and, therefore, has a much higher negative predictive value than sputum-smear microscopy. This means that the likelihood is low that a person with a negative Xpert MTB/RIF test has TB. It is important that clinicians interpret a negative Xpert MTB/RIF result differently than a negative sputum-smear microscopy result. Although no bacteriological test can completely rule out TB, a clinical diagnosis needs to be considered for a much smaller proportion of persons who are negative by Xpert MTB/RIF testing than for persons who are negative by sputum-smear microscopy (see Chapter 3). The most sensitive algorithm is to use CXR for initial triaging regardless of symptoms, followed by Xpert MTB/RIF testing (see Algorithm 10). However, this algorithm is more expensive and results in a higher number of false-positive results than sequential triaging with symptoms and CXR. FIG. 2. Algorithm options for triaging patients with respiratory complaints consistent with TB a Triage algorithm Cost per true case detected Yield of true-positive results Yield of false-positive results 1. Cough followed by microscopy 2. Cough followed by CXR followed by microscopy 3. Any TB symptom followed by microscopy 4. Any TB symptom followed by CXR followed by microscopy 5. CXR followed by microscopy 6. Cough followed by Xpert MTB/RIF testing 7. Cough followed by CXR followed by Xpert MTB/RIF testing 8. Any TB symptom followed by Xpert MTB/RIF testing 9. Any TB symptom followed by CXR, followed by Xpert MTB/RIF testing 10. CXR followed by Xpert MTB/RIF testing CXR: chest X-ray.", "15 Chest radiography in tuberculosis detection a The figure shows the potential yield of triage and the subsequent diagnostic evaluation for TB based on using the indicated tools. The cost and yield indicator values are based on a hypothetical scenario of a triage population of 100 000 with a TB prevalence of 0.5% (500 cases/100 000 population). (Details are available in Annex 1.) The Cost indicator ($) corresponds to the cost per true case detected for each algorithm; $ corresponds to the algorithm with the lowest relative cost per true case detected and $$$$$ corresponds to the algorithm with the highest cost per true case detected. The True-positives indicator (green +) corresponds to the yield of true TB cases (with liquid culture as the gold standard); one green + corresponds to the algorithm with the lowest yield of true-positive cases and five green +++++ signs correspond to the algorithm with the highest yield of true-positive cases. The False-positives indicator (red +) corresponds to the number of false-positive bacteriological test results; one red + corresponds to the algorithm with the lowest number of false-positive test results and five red +++++ signs correspond to the algorithm with the highest number of false-positive results. Note that true and false positive indicators within each algorithm are not proportional and can therefore not be directly compared to assess positive predictive values. Also note that predictive values change with prevalence. See Annex 1 for actual numbers with different prevalence. 2.3.3 Using chest X-ray after a negative bacteriological test result A negative initial bacteriological test result may require additional bacteriological testing (see Chapter 3). This can be done in parallel with a CXR if CXR was not done previously. For the diagnosis of non- bacteriologically confirmed TB, CXR has previously been recommended to be performed after a negative bacteriological test result and a trial treatment with broad spectrum antibiotics other than those used to treat TB (17, 18). However, trial treatment with broad spectrum antibiotics is not in line with general principles on the use of antibiotics, which should be reserved for treating a clear indication and not primarily used for diagnostic purposes. Trial treatment with antibiotics is particularly discouraged in children (22). Putting CXR at the end of a diagnostic algorithm may sometimes be the only option \u2013 for example in primary healthcare facilities where X-ray is not available and patients need to be referred to", "a secondary care facility. In this case, often patients with symptoms highly suggestive of TB and negative smear microscopy results are then referred to secondary care facilities for further evaluation with CXR. This approach is rational when infectious TB is the priority or if radiography access is limited. However, the approach can lead to delayed TB diagnosis and loss to follow-up during the diagnostic work-up, especially when a bacteriological test with low sensitivity is used, such as sputum-smear microscopy (which misses many true cases). One rationale for not doing a CXR before a bacteriological test is to avoid identifying a large group of people as possible TB patients via an early CXR, which can lead, in turn, to false-positive CXR-based clinical diagnosis of TB (see Sections 2.3.1 and 2.3.2, and Chapter 3). However, the risk of a false-positive clinical diagnosis can be reduced by using proper quality control as well as by improving access to sensitive and rapid molecular tests, or culture, or both, which can more effectively rule out TB than sputum-smear microscopy and can, therefore, reduce the number of cases diagnosed based on CXR findings. 2.3.4 Estimating the yield and cost to decide where to place chest X-ray in triaging for TB The judgement of whether to expand CXR use as part of triaging for TB and the decision of where to put CXR in a triaging algorithm need to be based on an assessment of the risks of overdiagnosis versus underdiagnosis, and in the context of resource demands, the availability of human resources, the accessibility of CXR, and the feasibility and cost effectiveness. It is also important to consider that if all tools included in a diagnostic algorithm are not located in the same physical location, patients risk being lost in the diagnostic pathway. A case study on CXR in TB detection algorithms in India is provided in box 3. It may be helpful to estimate for different triaging protocols the number of CXR investigations and number of bacteriological tests required (and related resource demands), as well as the potential yield (including true positives and false positives, and true negatives and false negatives; see Annex 1 for an example). Unfortunately, the scientific evidence about the performance and cost effectiveness of different triaging algorithms using CXR is limited. The ScreenTB tool (12), initially developed for systematic screening, can be used for preliminary modelling of the theoretical expected yield", "and related costs required for some triage algorithms and the epidemiological scenarios in a given setting. However, the assumptions (originally put in place for screening) may need to be changed, and the outputs of the tool are only indicative. The introduction of any new algorithm should be coupled with careful monitoring and evaluation of its performance, in terms of the yield and the proportion of detected cases that are bacteriologically confirmed (5).", "16 Chest radiography in tuberculosis detection BOX 3. Case study on chest radiography in the TB detection algorithms in India India has the highest TB burden of any country, representing 23% of the total global burden. Although policies requiring mandatory case notification, a new web-based information system and greater engagement with the private sector have led to significant recent increases in case notification, there is still a large case-detection gap. In response, the country is looking for ways to increase case detection, including developing more sensitive approaches for identifying persons who need to be evaluated for TB. CXR has, therefore, returned to the agenda after several decades of marginal programmatic use. CXR has long featured in TB detection in India, but its use has varied. In the 1960s, radiography was used for mass TB screening and clinical diagnosis of TB. These uses were accompanied by high rates of clinically diagnosed TB. Beginning in the 1990s, with the adoption of DOTS, CXR was still used to diagnose TB but less often because it was placed at the end of the recommended diagnostic algorithms, to be used only after multiple negative smear examinations and a trial course of antibiotics. Accordingly, the amount of training for providers dedicated to the use of CXR decreased substantially over the same period. When India launched its first national TB programme in 1962, District TB Officers were trained at the national level for 3 months. For more than 30 years, the main component of training aimed to help the officers develop skills in the CXR-based diagnosis of TB. After DOTS was introduced in the 1990s, under the Revised National TB Control Programme, training was gradually reduced to 2 weeks. The use of CXR was discouraged because previously TB had been overdiagnosed in the NTP when diagnosis was based on CXR. Consequently, the focus of training shifted to ensuring high-quality smear microscopy, and training in CXR vanished from the human resources development plan. Overall, this led to a decrease in the skills needed to evaluate CXRs, an inadequate infrastructure and availability of radiology, and minimal CXR monitoring and quality assurance, especially in peripheral areas. Throughout the period from the 1960s to the present, however, CXR has been widely used in the private sector, where it has been the preferred initial tool for TB detection, and it has also been used extensively for clinical diagnosis. No formal quality assurance", "procedures for CXR and clinical diagnosis in the private sector have been undertaken. In 2016, after programme evaluations suggested that only 5% of patients symptomatic for TB were screened completely using the existing diagnostic algorithms, and data from prevalence surveys suggested there would be an additional 30\u201340% diagnostic yield using CXR as a screening tool, the Ministry of Health and Family Welfare of India recommended revised diagnostic algorithms that feature CXR as an early triage tool for evaluating patients with suspected TB, to be used with bacteriological confirmatory evaluation and continued clinical assessment of bacteriologically negative patients. However, the implementation of the revised triage and diagnostic algorithms will likely be hampered by the limited availability of high-quality CXR. Currently, CXR technology is available only in the private sector and at the public sector referral level. Along with limited equipment for CXR, only limited personnel have been trained to deliver and interpret CXRs. Additionally, the financing for radiology services varies by state, and although many states have provisions for free-of-charge CXR in the general health budget for patients with suspected TB, some require fees from patients. T echnological innovations may provide future opportunities to address financial and human- resource capacity gaps in CXR access, including by using digital CXR in combination with telemedicine. More information can be found in the following resources: \u2022 International standards for tuberculosis care, third edition (20) \u2022 the website for the Practical approach to Lung Health (known as P AL) (29) \u2022 Xpert MTB/RIF policy update and implementation manual (2, 3) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Systematic screening for active tuberculosis: an operational guide (5) \u2022 ScreenTB tool: target prioritization and strategy selection for tuberculosis screening (12).", "17 Chest radiography in tuberculosis detection 3. CHEST X-RAY AS A DIAGNOSTIC AID 3.1 Chest X-ray as a diagnostic aid for respiratory and other intrathoracic diseases As discussed in Chapter 2, people with respiratory symptoms who are seeking care need to be evaluated not only for TB but for all relevant respiratory diseases, which may include, for example, non-TB infections, diseases of airflow obstruction (such as chronic obstructive pulmonary disease or asthma), neoplasms (such as lung cancer or pulmonary metastasis), occupational lung diseases (such as silicosis) or bronchiectasis. CXR is a useful diagnostic aid for several of these conditions, as well as for diseases that affect extrapulmonary intrathoracic structures (such as mediastinal lymph nodes, the pleura or pericardium). Good quality chest radiographs are essential for proper evaluation. CXR should be seen as a tool that can be used in comprehensive pathways for diagnosing respiratory and other intrathoracic diseases. Beyond algorithms for TB diagnosis and treatment, protocols are needed for the proper referral and management of other diseases, in line with the principles of the practical approach to lung health (29). CXR is an essential health technology that should be accessible to all. However, because access remains limited in many settings, and it may be available only in tertiary care, the choice to use CXR as a diagnostic aid clearly depends on the availability of and access to CXR (see Chapter 6). 3.2 Chest X-ray as a complement to bacteriological TB tests It must be underscored that although CXR is a useful adjunct in diagnosing TB, CXR alone cannot establish a diagnosis. Bacteriological confirmation of TB should always be attempted. The triage algorithms described in the previous chapter show only the steps leading to an initial bacteriological test, but not the subsequent bacteriological testing and clinical assessment that may be required. Additional bacteriological testing may be required after a negative initial bacteriological result. This is especially relevant if the initial test is sputum-smear microscopy, which has low sensitivity. For such patients, subsequent Xpert MTB/RIF testing or culture should be done if the clinical suspicion of TB is moderate to high \u2013 for example, due to CXR findings consistent with TB. Although Xpert MTB/RIF testing is more sensitive than smear microscopy, the sensitivity of the test in a given setting depends on the prevalence of smear-negative TB in the patient population; this is because the Xpert MTB/RIF assay is highly sensitive for", "smear-positive TB but only moderately sensitive for TB that is smear negative (2). Hence, repeated testing should be considered using the Xpert MTB/RIF assay or culture, or both, after an initially negative Xpert MTB/RIF assay or culture. Culture can improve the sensitivity of bacteriological confirmation, although it typically takes 6\u20138 weeks before results are available. Considerations for sequential bacteriological testing and suggested bacteriological test algorithms, including for diagnosing drug-resistant TB, are included in WHO\u2019s framework on implementing TB diagnostics as well as in the International standards for tuberculosis care (20, 33). Making a clinical diagnosis based on medical history (symptoms, TB exposure, risk markers), signs and CXR findings is sometimes reasonable in persons in whom TB cannot be ruled out despite negative bacteriological tests. In combination with clinical assessment, CXR may provide important circumstantial evidence for clinical diagnosis (20). Repeated CXR examination after a period of time could be considered, as interpretation of image changes could aid in clinical evaluation for TB and other diagnoses. Clinical diagnosis is particularly relevant in certain groups for whom it can be difficult to confirm a TB diagnosis with a bacteriological test. This includes patients for whom bacteriological tests tend to have lower sensitivity, such as people living with HIV or people with other immune-compromising conditions. It also includes patients from whom it is difficult to collect samples for bacteriological confirmation, such as young children. Moreover, for seriously ill patients (particularly persons with HIV infection), a clinical decision to start treatment often must be made without waiting for test results. Such patients may die if appropriate treatment is not begun promptly (4, 20, 23). In such patients, CXR can be particularly useful", "18 Chest radiography in tuberculosis detection as a diagnostic aid given the rapidity with which it delivers results. The risks associated with a delayed or missed TB diagnosis in these groups can be higher than the risks associated with a possible false-positive clinical diagnosis, which means that a clinical diagnosis made with a relatively low positive predictive value may be acceptable. However, it should be noted that the accuracy of CXR in these groups may be lower than in other groups. If a patient is not critically ill, follow-up bacteriological testing, repeat CXR and re- evaluation of TB and differential diagnoses should be considered (19, 20). Patients in whom a clinical diagnosis of TB has been made should be followed closely to ensure that a non-TB disease has not been misdiagnosed and left untreated. Follow-up should include repeat clinical and radiological assessment. For those who deteriorate or fail to improve, repeat bacteriological testing for TB should be considered (that is, to ensure the initial results were not falsely negative) and also diagnostic testing for non-TB diseases. Quality assurance for clinical TB diagnoses is important (see Chapter 5), both to not miss TB cases and to avoid overdiagnosis. Unnecessary TB treatment should be avoided to protect patients from harm and avoid wasting resources, both for patients and society. Moreover, making a false-positive clinical TB diagnosis when the illness has another cause can delay proper diagnosis and treatment of the true illness \u2013 for example, lung cancer (34). When an abnormality is present on CXR it is important to consider all possible differential diagnoses. Persons with confirmed or unconfirmed TB may have other concurrent lung conditions. Quality assurance involves ensuring high-quality CXR as well as high-quality CXR reading (35), (36). Quality and standardization can be improved by conducting multidisciplinary clinical rounds, convening groups of diagnostic experts and implementing peer review procedures. Monitoring and evaluation are essential. A useful indirect indicator of quality is the proportion of TB cases that have not been bacteriologically confirmed. A high proportion of clinically diagnosed TB may indicate overdiagnosis. A low proportion may indicate underdiagnosis. However, there is no established benchmark for the appropriate proportion of cases of bacteriologically confirmed TB. 3.3 Chest X-ray as part of a comprehensive diagnostic pathway in children CXR is useful in the diagnostic evaluation of TB as well as other intrathoracic diseases in children, especially younger children, in whom bacteriological evaluation", "is commonly negative. It should be part of a comprehensive diagnostic pathway that includes multiple steps, beginning with clinical assessment, the assessment of risk factors and exposure history, and CXR and bacteriological tests, as required. In most cases, children with TB have radiographic changes suggestive of TB (22). Adolescent patients with TB have radiographic changes similar to those seen in adult patients. Good-quality CXRs are essential for proper evaluation (22). A lateral CXR view may be required, especially in younger children and when bacteriological confirmation is challenging. For example, children younger than 4 years are more likely to have primary TB, and a lateral view will be important in identifying mediastinal or hilar lymphadenopathy (37). Details are provided in the Guidance for national tuberculosis programmes on the management of tuberculosis in children (22). As with adults, there are no specific features on clinical examination that can confirm that the presenting symptoms are due to TB. Every effort should be made to confirm the diagnosis of TB in a child using whatever specimens and laboratory tests are available (22). The Xpert MTB/RIF assay should be used as the initial test in all children suspected of having TB, regardless of their HIV status (2). It should be noted that children living with HIV have a substantially elevated risk of TB. The approach to diagnosing TB in children living with HIV is essentially the same as for diagnosis in HIV-negative children. However, this approach can be more challenging in children living with HIV because there is a high incidence of acute and chronic lung diseases other than TB; because children with HIV may have lung disease of more than one cause (multimorbidity), which can mask their response to therapy; and because there is an overlap of radiographic findings in TB and from other HIV-related lung diseases, making CXR less specific for detecting TB in children with HIV (22). CXR quality assurance can be especially challenging when CXR is used in children. Radiographers and medical staff require special training on taking and reading CXRs in children, and ensuring this training", "19 Chest radiography in tuberculosis detection occurs is a particular challenge in low- and middle-income countries where there are few paediatric- orientated radiologists. More information can be found in the following resources: \u2022 International standards for tuberculosis care, third edition (20) \u2022 Guidance for national tuberculosis programmes on the management of tuberculosis in children, second edition (22) \u2022 Xpert MTB/RIF policy update and implementation manual (2, 3) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23).", "20 Chest radiography in tuberculosis detection 4. CHEST X -RAY AS A SCREENING TOOL FOR PULMONARY TB 4.1 Chest X-ray as a sensitive tool for screening for active TB Systematic screening for active pulmonary TB is defined as the \u201csystematic identification of people with suspected active TB in a predetermined target group, using tests, examinations or other procedures that can be applied rapidly\u201d (4). Unlike the evaluation of those who actively seek care for respiratory symptoms (see triaging, Chapter 2), the systematic screening of individuals for TB is typically initiated by a provider and offered in a systematic way to an apparently healthy target group that has been determined to have a high risk of TB. Systematic screening implemented within health facilities is a special systematic screening situation in which specific risk groups at high risk of TB are targeted for screening among people seeking care in health facilities \u2013 for example, people being treated for diabetes or people living with HIV who are attending a clinic to receive antiretroviral therapy. Systematic screening of all people seeking care in an outpatient department may be considered in a setting where TB is highly endemic. Such an approach can also be seen as aggressive triaging for TB; the same principles for choosing an appropriate screening algorithm apply. Systematic screening outside health facilities \u2013 such as in the community or in special institutions such as prisons or shelters for homeless people \u2013 is often labelled active case finding, which refers to a provider- initiated approach that actively reaches outside the health services. Such screening can help find prevalent cases of TB in the community that might otherwise go undiagnosed and untreated. It often requires screening a large number of people who do not have TB. Costs can be high, and the risk of a false- positive diagnosis is high when TB prevalence in the screened group is low or moderate (4). Because of this, choosing an accurate screening algorithm is critical, and there are specific considerations involved, including how well the screening and diagnostic tools perform in the population to be screened, the trade- off between risks and benefits to the person being screened, the ability of the screening algorithms to detect TB without risking overdiagnosis, and the feasibility and costs (4, 5). WHO\u2019s guideline Systematic screening for active tuberculosis: principles and recommendations describes 10 algorithms for screening for TB (4). Eight options", "include a symptom screen as the initial test (screening either for cough lasting longer than 2 weeks, or screening for any symptom consistent with pulmonary TB, including cough of any duration, haemoptysis, weight loss, fever or night sweats), and two options use CXR as the initial screening test. If symptom screening is used initially, then CXR can be used as a second screen to improve the pre-test probability of the subsequent diagnostic test and to reduce the number of people who need to undergo further diagnostic evaluation. See box 4 for an example of the use of CXR as a tool for TB screening in migrants and refugees. As discussed in Chapter 2, symptom screening has a low sensitivity, especially for detecting TB early, which is a primary objective of systematic screening. Nevertheless, symptom screening is a low-cost and feasible approach that may be the only option in some situations. CXR, however, is a good screening tool for pulmonary TB because of its high sensitivity (87% to 98%, depending on how the CXR is interpreted) (4), meaning that up to 98% of those with culture-positive TB who undergo CXR will have an abnormal result. From the perspective of the person being screened, CXR is a valuable tool because it provides rapid screening results for a range of medical conditions beyond TB (21). Like symptom screening, CXR has low specificity in an active case-finding situation (46% to 89%, depending on how it is read) (4), meaning that a significant proportion of individuals without TB will have an abnormal test result. This is due, in part, to the fact that CXR identifies many types of lung abnormalities, whether due to TB or to other lung conditions. For this reason, CXR should be used with a bacteriological confirmatory test that has high sensitivity and specificity for TB. However, as discussed in Chapter 2, it is unavoidable that some proportion of persons who screen positive by CXR and who are negative by bacteriological tests will be diagnosed based on CXR and clinical criteria alone. Such patients should be periodically re-evaluated to assess response to treatment for TB and to exclude other diseases that might explain the", "21 Chest radiography in tuberculosis detection radiographic findings. A significant proportion of those with a clinical diagnosis may not, in fact, have TB and, thus, may be treated unnecessarily. At the same time, some of the true TB cases will be missed. The proportions of false-positive and false-negative cases found through screening will depend on the TB prevalence in the screened group, on the quality of the laboratory test, and on the rigour used in making clinical diagnoses, including the quality of CXR and CXR reading, as well as the quality of clinical evaluation (4). It is essential to ensure that the diagnostic quality is high, including for clinical diagnosis. It is also important that people invited for screening are well informed about the diagnostic challenges. This is particularly important in the context of screening as compared with triaging, for two reasons: screening is normally provider-initiated rather than patient-initiated (which leads to particular ethical considerations) and the prevalence of TB in the tested group tends to be much lower (which leads to lower positive predictive values). Although CXR is the preferred screening tool from the viewpoint of test accuracy, it can be expensive and logistically challenging to use, especially during active case finding when screening is done as an outreach activity outside the health services. The best choice of screening tool for any given situation depends on several factors, including the setting where screening is to be done, the populations to be screened and their epidemiology of TB and associated risk factors, the resources available (such as, human or financial), and the feasibility of various screening options. CXR is a good choice in most screening scenarios, particularly those based in the healthcare setting (see Case study 2) or where it is feasible to utilize mobile X-ray technology, but it will not be feasible in some scenarios. WHO\u2019s Systematic screening for active tuberculosis: an operational guide provides some guidance for the processes of planning screening and choosing an appropriate screening approach (5). The operational guide (5) and the ScreenTB tool (12) can be used to model the potential yield of true-positive and false-positive cases from various screening approaches, as well as costs, which can help in prioritizing the risk groups to be screened and choosing a screening algorithm. As with the discussion of optimizing triage algorithms in section 2.3, the introduction of any new algorithm for screening should be coupled with", "22 Chest radiography in tuberculosis detection BOX 4. Case study on the International Organization for Migration\u2019s experience of using digital chest radiography and teleradiology to screen migrants for TB. The International Organization for Migration (IOM) conducts health assessments for selected immigrants and refugees during the process of resettlement. A key component of the health assessment is radiological screening for TB for migrants from countries with a significant burden of TB. CXR is performed on all adults and on children with indications for TB evaluation (such as a positive tuberculin skin test or interferon-gamma release assay, or being a close contact of a person with TB or HIV). For the detection of TB, an abnormal CXR suggestive of TB is the main criterion for referral for sputum-smear microscopy and culture examination; clinical suspicion is the main criterion for referral for cases with a normal CXR. Because this health screening is conducted in an apparently healthy population, TB is usually detected during an early phase of disease, and the findings on CXR are often subtle. Skilled radiologists experienced in interpreting screening CXRs for TB are essential. The difficulty in finding appropriately skilled radiologists, especially in rural areas, prompted the IOM to develop a Global T eleradiology and Quality Control Centre in 2012. The aim was to standardize and optimize the quality of CXR used across all IOM health assessments. The centre utilizes a teleradiology system, with web-based applications and live chat for communications and to transfer digital images and provide CXR reports in real time. The centre provides primary CXR reading if necessary, with a turnaround time of 1 hour, as well as quality control and radiology-related technical support to IOM health-assessment field operations globally. From 2011 to 2015, IOM conducted health assessments for more than 1.5 million people, of which 1.2 million immigrants and refugees were screened for TB using CXR as part of their health assessment. Among those screened, 5% had CXR findings consistent with TB, and among those almost 7% were diagnosed with TB. Among diagnosed TB cases, 84% were bacteriologically confirmed. The majority were culture-confirmed smear-negative cases. These experiences demonstrate the potential for using CXR to screen a large group of apparently healthy individuals for TB and find a significant number of cases. The high proportion of culture-confirmed smear- negative TB indicates the low sensitivity of smear microscopy and that it is possible to maintain a high standard", "of bacteriological confirmation with culture. The IOM experience also shows the potential for digital and communication technologies to increase access to CXR and to skilled radiology services globally. However, nearly 400 immigrants or 164 refugees needed to be screened to detect 1 case of TB. The cost effectiveness of this type of mass screening needs to be considered. The TB detection rate was 2.5 times higher in refugees than in immigrants, which indicates that screening targeted high-risk groups will be more cost-effective than screening all migrants. 4.2 Chest X-ray screening in TB prevalence surveys In the specific context of a national TB prevalence survey, in which a country\u2019s entire adult population is sampled and tested to determine the population prevalence of TB, screening is applied to identify individuals who should undergo bacteriological examinations. CXR is the most sensitive screening tool for identifying those survey participants with a high probability of having TB. For diagnosis, combining CXR and symptom checklists for screening (with, typically, a positive result in either category being sufficient to warrant further testing) with culture or an alternative bacteriological test with high sensitivity (such as the Xpert MTB/RIF assay), will generate the most accurate prevalence estimate for bacteriologically positive TB (which is the objective a TB prevalence survey). CXR should, therefore, be used for all participants in a survey, regardless of their symptoms or risk markers (21). It should be noted that prevalence surveys Total of 1 204 569 screened for TB with CXR: 836 462 immigrants and 368 107 refugees 63 884 (5.3%) had findings suggestive of TB: 30 172 (4%) immigrants and 33 712 (9%) refugees 4 341 (6.8%) diagnosed with TB: 2 096 immigrants and 2 245 refugees 84% laboratory confirmed (40% through smear, 60% through culture)", "23 Chest radiography in tuberculosis detection generally do not include children (usually defined as less than 15 years of age), due to ethical concerns and because they require distinct screening and diagnostic procedures, so survey findings do not represent the entire population and cannot be extrapolated to the younger age group. The screening strategy recommended by the WHO Global T ask Force on TB Impact Measurement is shown in Fig. 3. Those persons with abnormalities on CXR and/or found to have TB-compatible symptoms during the questionnaire screening are eligible for sputum examination with the Xpert MTB/RIF assay or culture, or both. Those who do not have abnormalities or symptoms suggestive of TB during screening are not eligible for bacteriological testing and do not submit sputum samples. For more information, see T uberculosis prevalence surveys: a handbook (21). FIG. 3. WHO\u2019s recommended screening strategy for TB prevalence surveys (21) CXR: chest X-ray. A screening strategy using symptom screening without CXR screening is not recommended because it will underestimate the true prevalence of TB. Between 23% and 70% of bacteriologically positive cases detected in recent surveys had chronic cough, meaning that, on average, half of bacteriologically confirmed cases will be missed by symptom screening alone (see Annex 2) (21). T o increase sensitivity, intentional overreading of CXRs should be encouraged in the context of a prevalence survey. That is, participants with any lung abnormality (even if it may not be considered typical of TB) should be referred for bacteriological examination. Overreading should ensure that almost all potential TB cases are referred for sputum examination. Because TB in an immunocompromised person with a high risk of TB, such as an HIV-positive individual or, to a lesser extent, a person with diabetes, often shows atypical manifestations in a CXR, using CXR abnormalities suggestive of TB to identify individuals eligible for sputum examination may not be sensitive enough. Therefore, the recommended definition for screening is any CXR abnormality in the lung (21). Follow-up of participants with abnormal CXR and negative bacteriological exams is sometimes warranted. ABNORMAL CXR and/or POSITIVE SYMPTON SCREEN NO BACTERIOLOGICAL TESTING BACTERIOLOGICAL TESTING Microscopy culture, Xpert MTB RFI YES NO", "24 Chest radiography in tuberculosis detection 4.3 Chest X-ray to rule out active TB before treating latent infection Due to the crucial importance of excluding active TB before initiating treatment for latent TB infection (LTBI), one of WHO\u2019s recommendations for managing LTBI in resource-rich settings with a TB incidence of < 100 cases/100 000 population states that before initiating treatment for LTBI, individuals should both be asked about any symptoms of TB and should undergo CXR. Individuals with TB symptoms or any radiological abnormality should be investigated further for active TB and other conditions. For more information, see the Guidelines on the management of latent tuberculosis infection (24). Guidelines for managing LTBI in resource-poor high-burden settings are being developed; presently, in such settings CXR is not usually used for evaluating asymptomatic children under 5 years of age. Using the combination of any abnormality in a CXR and/or the presence of any symptoms suggestive of TB (that is, any one of cough, haemoptysis, fever, night sweats, weight loss, chest pain, shortness of breath or fatigue) offers the highest sensitivity and negative predictive value for ruling out TB (24). More information can be found in the following resources: \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Systematic screening for active tuberculosis: an operational guide (5) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 Guidelines on the management of latent tuberculosis infection (24) \u2022 Screening chest X -ray interpretations and radiographic techniques (10).", "25 Chest radiography in tuberculosis detection 5. TECHNICAL SPECIFICA TION, QUALITY ASSURANCE, QUALITY CONTROL, AND SAFETY 5.1 Technologies for chest X-ray and technical specifications WHO first specified a basic radiological system in 1975. The concept was developed further with a series of revisions. WHO\u2019s guiding principles in designing radiological units have been: \u2022 the radiological image must be high quality; \u2022 the equipment must be safe for patients and personnel; \u2022 the equipment must be easy to install and use; \u2022 required equipment maintenance should be minimal and quality assured; \u2022 if necessary , it must be possible to use the equipment with an unreliable electricity supply. T wo types of technology are used for CXR: analogue (that is, a system using film) or digital. It is important to highlight that both of these technologies employ the same principle of X-ray production (which is non-digital); the difference is the method of recording the result. In conventional systems, the result is recorded and displayed on an X-ray film but in digital systems, the result is recorded on a detector and displayed in a digital format on a computer screen (and it can also be printed on X-ray film or paper or sent to a digital device). Digital systems have several advantages over conventional systems. They reduce procedure time, have very low running costs (particularly when a hard copy image is not needed), save on staff requirements because the system is more user-friendly, produce superior image quality, give a lower radiation dose, allow for easier archiving and are more environmentally friendly. Moreover, they allow for telemedicine solutions and can be used for computer-aided reading. In 2000, WHO published the Consumer guide for the purchase of X-ray equipment (38), a comprehensive document that was aimed at small hospitals and large primary healthcare centres. The document covered not only technical specifications but also guidance on infrastructure, staffing and protection from radiation. However, because affordable digital technologies were not widely available for resource-poor settings at the time, the guide recommended only conventional X-ray technology with a manual or automatic film processing and development system. In 2016, WHO developed technical specifications for the 61 essential medical devices needed by healthcare facilities (39). The specifications for digital imaging systems in that document should help countries procure appropriate equipment. It was compiled by WHO in collaboration with a working group of experts, and will be continually updated. Among", "the 61 devices, 6 diagnostic X-ray-related devices are included (as of 29 September 2016): \u2022 the stationary basic diagnostic X -ray system, digital; \u2022 the mobile basic diagnostic X -ray system, digital; \u2022 the stationary basic diagnostic X -ray system, analogue; \u2022 the mobile basic diagnostic X -ray system, analogue; \u2022 the darkroom automated X -ray film processor; and \u2022 the daylight automatic X -ray film processor. Basic radiography is an essential technology in primary care, such as at health centres and district hospitals. The basic radiography unit (the stationary digital diagnostic X-ray system) has much wider functions than CXR, such as to investigate trauma or gastrointestinal diseases and to perform interventions, such as thoracic intubation, and the fixation or manipulation of fractures and dislocations. Mobile digital basic X-ray systems that can provide radiology services outside the radiology unit, such as in an operating theatre or intensive care unit, are listed in WHO\u2019s 2016 technical specifications as the second unit of radiography needed for hospitals.", "26 Chest radiography in tuberculosis detection In some facilities it is appropriate to have a CXR-specific stationary unit. WHO\u2019s specifications for stationary digital CXR systems are not available, but will be developed by WHO and its partners. Moreover, WHO\u2019s guidelines on radiography are limited to medical facilities. WHO is developing specifications for portable X-ray units, which are already widely used in small medical facilities, for home care, in military and disaster relief operations, for systematic TB screening and for TB prevalence surveys. The WHO Global T ask Force on TB Impact Measurement strongly recommends that countries do not use fluoroscopy or mass miniature indirect radiography for TB screening because these require a higher radiation dose (21). Since 2009, all national TB prevalence surveys, without exception, have adopted direct CXR technology. 5.2 How to choose chest X-ray technology There are many factors to consider when choosing the appropriate X-ray equipment. \u2022 Settings: For frontline hospitals and health centres, a stationary basic digital diagnostic X-ray system should be considered for the first X-ray unit, as X-ray technology has many diagnostic uses beyond CXR. An X-ray unit used only for CXR could be installed in the radiology department when the demand for CXR is high. For field use, options include a stationary X-ray unit (either in an X-ray van or container) or a portable unit. The choice depends on the accessibility of field sites, a country\u2019s regulations, the climate (temperature) and the daily demand for CXR images. \u2022 Costs: Costs depend on several factors. It is useful to think about the entire lifetime of the equipment when considering costs. Different technologies have varying levels of initial investment and running costs (including requirements for consumables, operational costs and costs for maintenance and parts). Digital systems have a higher initial cost but often offer savings on consumables (particularly when a hard copy of the CXR image is not necessary) and human resources. \u2022 Duration of use: Although X-ray equipment is sometimes acquired for a specific purpose or activity, such as for a systematic screening campaign or a prevalence survey, it should be assumed that it will be used for a much longer time period and for other purposes. Therefore, its utility should be considered in terms of its general use. \u2022 Field conditions: If the equipment is to be used in the field, important factors to consider are portability and power requirements. \u2022 Personnel: It", "is important to consider whether skilled personnel will be available to conduct CXR examinations, read the results and maintain the equipment in the setting in which it will be used. \u2022 Radiation exposure: Although none of the options present dangerous levels of radiation, newer digital technologies provide lower exposure to radiation. \u2022 Throughput capacity: Digital systems are good for tasks with a heavy workload \u2013 such as a prevalence survey, hospital-based systematic screening or active case finding in the community \u2013 because they shorten the processing time. \u2022 Availability of maintenance: Particularly for digital equipment, ensuring maintenance after the initial 1-year warranty period can be difficult in countries where maintenance services are scarce. 5.3 Computer-aided detection of TB New technologies for analyzing the results of CXR evaluations are being developed, including computer- aided detection (CAD) software that can analyze digital CXR images for abnormalities and the likelihood of TB being present. Such technology could help reduce interreader variability and delays in reading radiographs when skilled personnel are scarce. As of 2016, WHO provides no recommendations on using CAD for TB. A systematic review of five peer reviewed articles published in 2016 concluded that the evidence of CAD\u2019s diagnostic accuracy is limited by the small number of studies of the single commercially available CAD software (CAD4TB, Delft Imaging Systems, Veenendaal, the Netherlands). There were also important methodological limitations to the studies and their findings had limited generalizability (40). T o determine whether WHO should initiate a process to develop guidelines on CAD, WHO commissioned an extended systematic review to evaluate", "27 Chest radiography in tuberculosis detection both published and unpublished studies assessing CAD as a tool for evaluating persons with suspected TB and for TB screening (41). The following PICO questions were formulated (PICO refers to population, intervention, comparator, outcome). 1. What is the diagnostic accuracy of CXR interpreted by CAD for detecting TB confirmed with culture or a molecular test? 2. Is the diagnostic accuracy of a CXR analyzed with CAD superior , inferior or equivalent to that of a CXR interpreted by a human reader for detecting TB confirmed by culture or a molecular test? The review stratified results by use-case: in triage use-case studies, CAD was used for evaluating persons with suspected TB (that is, persons seeking care for TB symptoms); in screening use-case studies, it was used to screen populations at risk that may not be seeking care. The review focused on CAD4TB, the only commercially available CAD program for TB. CAD4TB analyses a digital CXR and produces an abnormality score ranging from 0 to 100, with higher scores indicating greater likelihood of TB. A threshold score is the abnormality score below which TB is considered ruled out. For this to be a generalizable diagnostic test, one would predefine a threshold for each use-case. However, threshold scores are currently not preselected by the test developers. Studies were identified through four medical databases as well as the developer of CAD4TB software, projects supported by the Stop TB partnership and researchers in the field. Of the 542 identified citations and studies with unpublished data, 13 were included in the systematic review: 5 published peer reviewed papers, 4 published conference abstracts and 4 unpublished studies. Seven studies were triage use- case, and 6 were screening use-case, of which 6 and 3, respectively, had results that addressed the PICO questions. Results were considered in light of the potential for bias and applicability concerns, and assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) approach (http:// www.quadas.org). A number of important methodological limitations were identified for both use-cases during quality assessment. The main sources of concern about the potential for bias and limited applicability were the inappropriate exclusion of participants (particularly in screening use-case studies) and how the threshold scores had been operationalized, in particular the use of threshold scores that were not prespecified. Concerns about generalizability also arose from the use of non-commercially available versions of CAD4TB, and", "from training staff and evaluating the software for CXR within the same study population. Studies were not equally affected by these methodological limitations. Overall, reviewers found that few studies used CAD4TB the way it will be used in the field \u2013 that is, with the most up-to-date commercially available version, with a prespecified threshold score and without having undertaken a pilot study to determine which threshold score to use. Furthermore, there was limited or no information about the performance of CAD4TB in several subgroups of interest, including people living with HIV and different age groups, particularly for the screening use-case studies. Finally, data disaggregated by sex or smear status were not available. No pooling of data was done due to the methodological heterogeneity of the reviewed studies, as well as to the low number of studies for each version of CAD4TB. Across versions, the software achieved high sensitivity for both use-cases, but with variable specificity. The sensitivity and specificity of the human CXR readers whose performance was compared with that of CAD4TB were variable. In a number of studies, CAD4TB\u2019s threshold score was set to match either the sensitivity or specificity of the human readers, thus limiting the comparisons of accuracy that could be made between the software and human readers. The software\u2019s sensitivity was similar to that of human expert readers in the triage use-case, but it was less specific. Performance varied when compared with non- expert readers. For the screening use-case, data were insufficient to draw conclusions about performance compared with humans. Based on the findings of the extended systematic review, WHO has decided not to initiate a guideline development process at the present time. CAD can be used for TB detection for research, ideally following a protocol that contributes to the required evidence base for guideline development. For this purpose, WHO plans to further specify the desirable characteristics of CAD for TB and develop advice on key research questions and appropriate study designs that can address those questions. Broad questions that should be addressed include the following:", "28 Chest radiography in tuberculosis detection \u2022 what is the added value of CAD in different places in the diagnostic pathway? \u2022 what is the added value of CAD in different populations and settings? \u2022 what should be the threshold scores for different populations or settings? \u2022 what needs to happen if a patient is symptomatic and a CAD assessment is negative? And what needs to happen if a patient is symptomatic and the CAD assessment is positive but the microbiological test is negative? \u2022 what is the cost effectiveness of CAD compared with human readers, considering different payment models? \u2022 what operational or implementation challenges exist for ensuring equitable access? \u2022 what needs to be done with preliminarily CAD-positive patients? For example, when would a human reader be engaged for final interpretation/reporting in each use case? \u2022 how could CAD be used as an aid to human CXR readers rather than as a replacement? T wo possible research strategies have been identified to generate evidence for WHO to issue recommendations on using CAD4TB. When new evidence has been generated, WHO will assess whether a guideline process should start. In strategy 1, data from individual patients and digital images from the higher quality studies identified in the extended review would be analysed independently of the CAD4TB developers, using the latest version of the software and pooling the results using a meta-analysis of individual patient data. Although this could provide evidence of sufficient quality for the triage use-case, it would be inadequate for the screening test use-case. Hence, a complementary undertaking in strategy 1 would be to compile a standard panel of CXRs taken from existing databases, and use this panel to evaluate CAD4TB. Potential data sources include completed or ongoing studies that utilize digital CXR in either a triage or screening use-case and also use the required reference standard as defined but that are not utilizing CAD software (in order to avoid the developers having access to the files for software training), TB prevalence surveys and other existing data sets of digital CXR files with appropriate pathology reference standards. The timeline of this strategy is estimated to be 1 year, but it needs to be further clarified. Strategy 2 would involve identifying planned or ongoing trials of CAD, or undertaking new studies, and integrating an evaluation of CAD into that research. The main focus would be the screening use-case. Design", "considerations that would ensure studies are of sufficient quality would include using predefined threshold scores according to the use-case; enrolling important subgroups of patients (defined by sex, age, HIV status, smear status); using CAD for all participants (in triage studies, this would include testing all participants with the reference test; in screening studies, this would include testing at least a subset of asymptomatic persons with the reference test); and for comparison, having human readers who are blinded to CAD scores and microbiological data, and using standardized categories for reporting CXR results. The timeline for this strategy is estimated to be 2\u20133 years but depends on the ability to integrate an evaluation of CAD into planned studies and the availability of funding. 5.4 Quality assurance and quality control There are two major areas of quality assurance for CXR: the quality of CXR imaging and the quality of CXR reading. The quality of CXR imaging is associated with the quality of the hardware being used and the quality of the techniques and applications. WHO provides technical specifications for X-ray machines and the equipment related to handling X-ray films and images, as well as checklists and workbooks (http://www. who.int/diagnostic_imaging/publications/en/). The WHO manual of diagnostic imaging is available on the website of the International Society of Radiology (http://www.isradiology.org/isr/books_technique.php) (7). Also, the Handbook for district hospitals in resource constrained settings on quality assurance of chest radiography was developed specifically for TB programmes (35). Quality control of CXR reading is also essential. Underreading leads to missed opportunities for diagnosing and treating TB, and overreading leads to excess burdens on TB laboratories, as well as possible false-", "29 Chest radiography in tuberculosis detection positive clinical diagnoses (10). Another resource developed specifically for quality assurance in TB programmes in district hospitals is the Handbook for district hospitals in resource constrained settings for the quality improvement of chest X-ray reading in tuberculosis suspects (36). In addition to qualifications such as diplomas, masters\u2019 degrees and fellowships, several distance-learning or self-training opportunities are available for ensuring quality control standards. Additionally, some professional societies have developed educational materials, and some of these are listed at the end of this chapter. The International Commission on Radiology Education, part of the International Society of Radiology, provides its own educational materials as well as links to materials from other sources (11). Standardized CXR reporting forms and peer review, which may be accomplished by holding regular conferences in hospitals or at local TB diagnostic committees, can be useful for standardizing reading and interpretations. In systematic TB screening campaigns and TB prevalence surveys involving non-specialist screening physicians or clinical officers, a specialist often assesses the primary reading (in what is known as a central reading system). Comparing laboratory results with CXR results can help to improve the quality of radiological screening and diagnosis. Monitoring the proportion of clinically diagnosed cases out of all TB cases can serve as an indicator of diagnostic quality. However, WHO has not defined formal procedures for internal or external quality assessment of CXR interpretation for TB screening and detection. 5.5 Safety A proportion of the X-rays used in radiography are absorbed by the body. The potential effects from ionizing radiation depend on the dose. At doses much higher than those of typical diagnostic imaging exams, the damage may be extensive enough to affect tissue function, and the damage may become clinically observable (for example, as skin reddening or burns). Effects of this type are called tissue reactions or deterministic effects, and they occur only if the radiation dose exceeds a certain threshold (42). The long- term risks from ionizing radiation include an increased risk of cancer. Direct CXR is a safe technology using a radiation dose of 0.1 mSv, which corresponds to 1/30 of the average annual radiation dose from the environment (3 mSv) and 1/10 of the annual accepted dose of ionizing radiation for the general public (1 mSv). As a point of reference, the radiation dose of one CXR is equivalent to or less than the radiation exposure received during", "return travel on an intercontinental flight. Therefore, exposure to the low radiation doses delivered to patients during a CXR poses a small risk of inducing tissue reactions or cancer in the years to decades following the examination (43). However, it should be noted that a linear non-threshold relationship is assumed between radiation exposure and the risks of effects of this nature. Based on this linear model, the probability of developing cancer is presumed to increase even following exposure to low doses of radiation, although the increase in risk is extremely small. Even though the individual risk associated with radiation exposure from CXR is low, when a large number of individuals are exposed, the associated risks may still constitute a public health issue. Children and pregnant women are especially vulnerable to ionizing radiation. Also, children have a longer life expectancy, resulting in a larger window for developing long-term radiation-induced health effects. When imaging small children and infants, exposure parameters should be adjusted from those used for adults to avoid using a higher dose than necessary. Unnecessarily high doses and their associated risks can be substantially reduced without affecting image quality by customizing exposure settings to deliver the lowest radiation dose necessary for providing an image that is fit for the clinical purpose. For pregnant women and the fetus, a CXR does not pose any significant risk, provided that good practices are observed, as the primary beam is targeted away from the pelvis (21). Due to the potential risks, the decision to expose patients to radiation during imaging procedures must adhere to two overall principles of radiation protection in medicine: justification and optimization. Justification means that the need for medical imaging should be assessed by weighing the expected benefits against the potential radiation risk, taking into account the benefits and the risks of alternative techniques that do not involve exposure to radiation. The procedure should be judged to do more good than harm. Optimization in medical imaging refers to keeping doses as low as reasonably achievable to obtain a useful image. X-ray personnel should at all times ensure that the benefits of an examination outweigh the potential risks from radiation exposure and that the patient is exposed to as little radiation as possible (14, 44, 45).", "30 Chest radiography in tuberculosis detection Staff performing CXR must be familiar with protection measures for themselves, for patients and for others who may be exposed. Important concepts in radiation protection include consideration of the following areas: Type of exposure, including: \u2022 medical exposure (exposure of clients, such as patients and study participants); \u2022 occupational exposure; \u2022 public exposure. Place of exposure, including: \u2022 controlled areas, such as the X-ray room and areas directly connected to X-ray rooms (used by X-ray staff and assistants during the X-ray examinations); \u2022 supervised areas, such as areas in the vicinity of the X -ray room, which are usually part of the X-ray department. Protection measures, including: \u2022 shielding \u2013 that is, barriers of attenuating material around the radiation source, such as concrete walls and lead-containing panels, curtains and windows; \u2022 distance from the radiation source. Preventing exposure for staff and the general public is particularly important when X -ray systems are taken outside of medical facilities, such as during systematic screening using mobile CXR in the community. Tuberculosis prevalence surveys: a handbook provides advice on how to ensure safety in the field (21). When a van with a full size X-ray system with safety and power features appropriate for a hospital is available, the safety standards applied for health facilities can be used. When portable CXR units are placed in non-shielded areas, then restricted areas should be set up, clearly marked and monitored under the guidance of the radiological unit of the survey team. Radiometers and film badge dosimeters should be used, and rules should be devised for how to direct the X-ray beam. More information can be found in the following resources: \u2022 Radiation protection and safety of radiation sources: international basic safety standards, interim edition (46) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 WHO\u2019s diagnostic imaging website (14) \u2022 WHO\u2019s Consumer guide for the purchase of X-ray equipment (38) \u2022 Handbook for district hospitals in resource constrained settings for the quality improvement of chest X -ray reading in tuberculosis suspects (36) \u2022 Handbook for district hospitals in resource constrained settings on quality assurance of chest radiography (35) \u2022 Communicating radiation risks in paediatric imaging (47) \u2022 International Commission on Radiology Education (42) \u2022 W orld Federation of Pediatric Imaging: TB resources (48) \u2022 Radiographic manifestations of tuberculosis: a primer for clinicians (9) \u2022 Screening chest X -ray interpretations and", "31 Chest radiography in tuberculosis detection 6. STRA TEGIC PLANNING FOR USING CHEST X-RAY IN NATIONAL TB CARE This chapter describes the strategic planning steps needed to introduce, expand, or systematize the use of CXR in TB care and prevention. Since CXR is not a TB-specific tool, developing a strategic plan for CXR should be done as a part of making general improvements to imaging services in the healthcare sector and within the broader framework of health-system strengthening and providing universal health coverage. This will increase the relevance and acceptance of investments in the technology and related capacity strengthening, and improve the overall efficiency and cost effectiveness of radiography services. Accordingly, the strategic planning process should involve all relevant stakeholders interested in introducing or expanding the use of CXR within the health sector. Including all stakeholders can be beneficial because different stakeholders will be able to utilize different sources of funding. However, this strategy may also be hampered by conflicting goals or expectations. If possible, the process needs to be integrated into the development of a national strategic plan for TB care, as well as into the broader national health plan. The level of integration will depend on the structure of the national health system and the level of decentralization in planning, as well as the timing of the strategic planning process at all levels. Strategic planning involves: 1. defining the objective of using CXR in the health system; 2. performing a situation analysis; 3. defining specific TB targets to which introducing, expanding or systematizing the use of CXR will contribute; 4. developing an operational plan, with a detailed budget and financing plan. Strategic planning for CXR should begin by defining the objective of using CXR within the health system and within the NTP national strategic plan \u2013 for example, it may be used to improve care for patients with respiratory diseases. Planning should then proceed by undertaking a situation analysis to understand the current state of and capacity for CXR in the country, the current epidemiology of TB and the possible contribution of CXR to TB care. T able 1 specifies the relevant questions that should be addressed by the situation analysis; the process should focus on those issues that are most relevant to the stated objective for current and planned use of CXR.", "32 Chest radiography in tuberculosis detection Area to assess Relevant issues to be addressed Potential information sources CXR capacity Determine the current state of CXR use in healthcare in the country, within both the public and the private sectors, including: \u2022 existing infrastructure, equipment (including specifications) and current workload and capacity; \u2022 existing human resources available to both conduct and read CXRs, and any available measures of their competencies; \u2022 existing internet connectivity capacity for e-health/telemedicine options, if applicable; \u2022 percentage of machines that are operational; \u2022 maintenance arrangements: how are maintenance issues reported and acted upon? What human resources and which budget (or budgets) are used for maintenance? \u2022 current financing: who pays for new equipment and for ongoing consumables, and from which budget (or budgets)? \u2022 what is the fee structure for end users, if any , in both the public and private sectors? \u2022 all stakeholders interested in using CXR and improving its use. Service availability and readiness assessment (known as SARA) surveys; national health insurance plans or other payment structures Determine existing national policies and regulations affecting the use of radiology , including: \u2022 its placement on the list of essential diagnostic services for the health service; \u2022 its placement on the list of essential medical devices; \u2022 quality assurance and quality control mechanisms; \u2022 safety policies and practices; \u2022 other existing national policies regarding the use of radiography , such as policies pertaining to health screening for immigrants or for occupational health screening. National guidelines on radiation safety; national screening policies for using CXR, such as to screen immigrants or for occupational health screening, or screening in prisons Map needs for human resources and capacity strengthening in the public and private sectors for introduction, scale up and quality assurance/quality control; consider: \u2022 radiologists and radiographers; \u2022 professional societies; \u2022 infrastructure for training and capacity strengthening; \u2022 capacity for e-health/telemedicine options. Professional societies that utilize CXR (such as radiologists and pulmonologists) Epidemiology of TB Determine the current epidemiology of TB in the region, including: \u2022 the geographical distribution of cases; \u2022 the age distribution of cases; \u2022 current case-detection gaps; \u2022 the current epidemiology of risk factors for TB; \u2022 any results from prevalence surveys or other research indicating the proportion of bacteriologically confirmed cases reporting no or vague symptoms of TB because this indicates the contribution that CXR could make to case detection; \u2022 CXR", "accuracy data from prevalence surveys or other research; \u2022 the profile of persons with suspected TB and where they would likely enter the health system, or how they could be detected through active case-finding initiatives (including children), as this will determine the current gap in CXR services and the potential workload of CXR. National TB surveillance data; WHO\u2019s global TB report; prevalence surveys; other relevant research findings from the country TB activities involving CXR Consider current and planned activities that require increased introduction or scale up of CXR and quality assurance in the country in terms of: \u2022 improving triaging; \u2022 improving the clinical diagnosis of TB; \u2022 improving the diagnosis of childhood TB; \u2022 implementing systematic screening in risk groups; \u2022 scaling up detection and treatment of latent TB infection. National strategic plan for TB; concept notes from the Global F und, or similar strategic planning for funding CXR: chest X-ray.", "33 Chest radiography in tuberculosis detection Based on the findings of the situation analysis, the TB control targets that CXR will contribute to need to be defined for its introduction, and for expanding or systematizing its use. For example, it should be specified whether the intended target is to increase case detection, rationalize the use of Xpert MTB/RIF testing or assist with the initiation of treatment for LTBI. Similarly, stakeholders not using CXR for TB should define their targets for introducing or expanding CXR use. The operationalization plan for integrating CXR into TB control should then be defined, beginning with the broader questions of CXR technology and placement in the healthcare system, and then using that information to proceed to address more detailed aspects of implementation, such as the following. \u2022 Where in the health system will CXR will be placed \u2013 for example, at the primary healthcare level, at the referral level, in hospitals, in mobile screening units? \u2022 Which CXR technology is best suited to the planned placement, or the desired improvement in the quality of existing CXR technology? This will be determined largely by the intended uses for CXR \u2013 for example, whether it will be used in routine care at primary healthcare centres or in a prevalence survey . \u2022 What additional infrastructure or equipment will be required, such as vans for mobile screening units or computers and internet connectivity for digital systems? \u2022 What is the approximate cost of such equipment, both in terms of procurement and ongoing operation and maintenance costs? Detailed budgeting comes later in the process (see below), but rough budget estimates are needed earlier to check that the proposed approaches are broadly affordable and cost effective. \u2022 What is the place of CXR in triaging, screening and diagnostic algorithms? What possible modifications could be made to current algorithms to make better use of CXR? \u2022 What is the expected increase in TB detection from the new algorithms or new placement of a CXR system? \u2022 What human resources are required for CXR use? \u2022 What are the initial training requirements and ongoing quality assurance requirements for CXR use? \u2022 Is there a need for technical assistance during the implementation of the operational plan? \u2022 What is the plan for monitoring and evaluating the use of CXR? \u2022 What is the plan for any operational research to be conducted in conjunction with", "CXR use in TB control? How will the associated data security and patient privacy issues be addressed? \u2022 What implementation steps are required to achieve the defined objectives and targets, and who will perform the steps and when? Along with this operational plan, a detailed budget needs to specify who will pay for the costs associated with using CXR, taking into account the different levels and budgeting processes of the entire health system. The budget should show the total cost of implementing and operationalizing CXR activities, the sources of funding and the funding gaps. The NTP , other departments of the ministry of health and other concerned ministries should work together to address the gaps in funding CXR for TB care to ensure the costs are not passed on to patients. Such costs can be catastrophic for individuals already facing severe economic and other stresses as a result of their illness. For more details, see WHO\u2019s Toolkit to develop a national strategic plan for TB prevention, care and control (49).", "34 Chest radiography in tuberculosis detection Annexes Annex 1. Yield and costs of triage algorithms in a hypothetical population of 100 000 with different TB prevalence levels The yields of true-positive, false-positive, true-negative and false-negative TB diagnoses (using liquid culture as the gold standard), and the cost per true case of TB detected, were modelled for different triage algorithms and different prevalence levels in a hypothetical population of 100 000 persons seeking healthcare. T able A1 displays the assumptions about test accuracy that are based on estimates from the systematic review done for the guideline on systematic screening for active TB (4). It should be noted that these estimates are from systematic screening studies (mainly TB prevalence surveys) and are likely to be different in a triage scenario. The reason for using these assumptions is that no data from systematic reviews are available for triage scenarios. The cost estimates are the same as the pre-set values on the ScreenTB tool. The ScreenTB tool (5, 12) can be used to model the yield and costs for these algorithms based on different assumptions. Table A1. Assumptions used to model the yield and costs per true case of TB detected Test Sensitivity Specificity Test costs a Operational costsa Cough screen 0.35 0.95 0 0.05 Any symptom screen 0.77 0.68 0 0.05 Digital chest X-ray 0.98 0.75 1.00 4.00 Sputum-smear microscopy 0.61 0.98 1.50 0.50 Xpert MTB/RIF assayb 0.92 0.99 10.00 7.00 a Costs are per person tested in US dollars. b Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). T able A2 displays the results of modelling with a TB prevalence of 250 cases per 100 000 population; T able A3 displays the results of modelling with a TB prevalence of 500 cases per 100 000 population; and T able A4 displays the results of modelling with a TB prevalence of 1 000 cases per 100 000 population.", "35 Chest radiography in tuberculosis detection Table A2. Yield and costs per true case of TB detected by triage algorithms in a hypothetical population of 100 000 with a TB prevalence of 250 cases/100 000a Algorithm True positive False positive False negative True negative Cost per case Number needed to screenb 1 (Prolonged cough SSM) 53 100 197 99 650 286 1 887 2 (Prolonged cough CXR SSM) 52 25 198 99 725 635 1 924 3 (Any symptom SSM) 117 638 133 99 112 592 855 4 (Any symptom CXR SSM) 115 160 135 99 590 1 582 870 5 (CXR SSM) 149 499 101 99 251 3 694 672 6 (Prolonged cough Xpert) 80 50 170 99 700 1 141 1 250 7 (Prolonged cough CXR Xpert) 79 12 171 99 738 671 1 266 8 (Any symptom Xpert) 177 319 73 99 431 3 112 565 9 (Any symptom CXR Xpert) 174 80 76 99 670 1 750 575 10 (CXR Xpert) 225 249 25 99 501 4 125 445 CXR: chest X-ray; SSM: sputum-smear microscopy; Xpert: Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). a The algorithms are described in detail in Chapter 2. b This is the number needed to screen to detect one true case. Table A3. Yield and costs per true case of TB detected by triage algorithms in a hypothetical population of 100 000 with a TB prevalence of 500 cases/100 000 a Algorithm True positive False positive False negative True negative Cost per case Number needed to screenb 1 (Prolonged cough SSM) 107 100 393 99 400 143 935 2 (Prolonged cough CXR SSM) 105 25 395 99 475 320 953 3 (Any symptom SSM) 235 637 265 98 863 296 426 4 (Any symptom CXR SSM) 230 159 270 99 341 795 435 5 (CXR SSM) 299 498 201 99 002 1 842 335 6 (Prolonged cough Xpert) 161 50 339 99 450 575 622 7 (Prolonged cough CXR Xpert) 158 12 342 99 488 347 633 8 (Any symptom Xpert) 354 318 146 99 182 1 562 283 9 (Any symptom CXR Xpert) 347 80 153 99 420 887 289 10 (CXR Xpert) 451 249 49 99 251 2 065 222 CXR: chest X-ray; SSM: sputum-smear microscopy; Xpert: Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). a The algorithms are described in detail in Chapter 2. b This is", "36 Chest radiography in tuberculosis detection Table A4. Yield and costs per true case of TB detected by triage algorithms in a hypothetical population of 100 000 with a TB prevalence of 1 000 cases/100 000a Algorithm True positive False positive False negative True negative Cost per case Number needed to screenb 1 (Prolonged cough SSM) 214 99 786 98 901 73 468 2 (Prolonged cough CXR SSM) 209 25 791 98 975 166 479 3 (Any symptom SSM) 470 634 530 98 366 149 213 4 (Any symptom CXR SSM) 460 158 540 98 842 401 218 5 (CXR SSM) 598 495 402 98 505 922 168 6 (Prolonged cough Xpert) 322 50 678 98 950 295 311 7 (Prolonged cough CXR Xpert) 316 12 684 98 988 185 317 8 (Any symptom Xpert) 708 317 292 98 683 786 142 9 (Any symptom CXR Xpert) 694 79 306 98 921 453 145 10 (CXR Xpert) 902 248 98 98 752 1 039 111 CXR: chest X-ray; SSM: sputum-smear microscopy; Xpert: Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). a The algorithms are described in detail in Chapter 2. b This is the number needed to screen to detect one true case.", "37 Chest radiography in tuberculosis detection Annex 2. Proportion of TB cases detectable through screening with chest X-ray or by screening for chronic cough The results of several recent prevalence surveys are presented below (T able B1), including the proportion of TB cases identified that reported various TB symptoms and that had abnormal CXR results. In particular, the column \u201cPercentage positive only by CXR\u201d demonstrates the potential contribution of CXR to TB detection over screening or triage based on symptoms alone. Table B1. Proportion of TB cases detectable through screening with chest X-ray or by screening for chronic cough among persons diagnosed with bacteriologically confirmed TB in recent TB prevalence surveys a Country No. of bacteriologically confirmed cases No. symptom positive, CXR positive No. symptom positive, CXR negative No. symptom negative, CXR positive Percentage positive by both CXR and symptoms Percentage positive only by CXR Percentage positive only by symptoms Cambodia 314 90 3 216 29 69 1 Ethiopia 110 45 12 53 41 48 11 Gambia 77 32 12 33 42 43 16 Ghana 202 67 15 85 33 42 7 Indonesia 426 220 25 181 52 42 6 Laos 237 111 7 119 47 50 3 Malawi 132 25 67 40 19 30 51 Mongolia 248 44 7 190 18 77 3 Myanmar 311 65 1 231 21 74 0 Nigeria 144 76 16 52 53 36 11 Pakistan 341 157 40 142 46 42 12 Rwanda 40 15 4 21 38 53 10 Sudan 112 44 8 43 39 38 7 Thailand 142 42 6 94 30 66 4 Uganda 160 63 16 81 39 51 10 Zambia 265 115 46 104 43 39 17 Zimbabwe 107 29 10 64 27 60 9 CXR: chest X-ray. a Data from country prevalence surveys or personal communication. 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Geneva: World Health Organization; 2016 (http://apps.who.int/iris/ bitstream/10665/205033/1/9789241510349_eng.pdf?ua=1, accessed 18 October 2016). 48. WFPI\u2019s TB Corner . In: World Federation of Pediatric Imaging [website]. Boston, MA: World Federation of Pediatric Imaging; 2015 (http://www.wfpiweb.org/Outreach/TBCorner.aspx, accessed 19 October 2016). 49. W orld Health Organization. T oolkit to develop a national strategic plan for TB prevention, care and control:", "WHO consolidated guidelines on tuberculosis. Module 3: diagnosis ISBN 978-92-4-010798-4 (electronic version) ISBN 978-92-4-010799-1 (print version) \u00a9 World Health Organization 2025 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). 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The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers\u2019 products does not imply that they are endorsed or", "recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Technical editing by Cadman Editing and design by Inis Communication", "iii Contents Acknowledgements v Abbreviations and acronyms vii Definitions ix Executive summary x 1. Introduction 1 1.1. Background 1 1.2. WHO TB diagnostic class determination and product prequalification 2 1.2.1 Pathway A 2 1.2.2 Pathway B 3 1.3. Testing classes and products 3 1.3.1 Initial tests for TB diagnosis with drug resistance detection 4 1.3.2 Initial tests for TB diagnosis without drug resistance detection 5 1.3.3 Follow-on tests for detection of TB drug resistance 5 1.3.4 Tests for TB infection 6 1.4. Scope of the document 7 1.5. Target audience 7 1.6. Scope of the document 7 1.7. Target audience 7 2. Recommendations for diagnosis of TB disease 9 2.1. Initial diagnostic tests for diagnosis of TB with drug-resistance detection 9 2.1.1 LC-aNAATs for detection of TB and resistance to rifampicin 9 2.1.2 Moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid 24 2.2. Initial diagnostic tests for diagnosis of TB without drug-resistance detection 37 2.2.1 Low-Complexity manual NAATs for detection of TB 37 2.3. Concurrent use of initial diagnostic tests for diagnosis of TB in People living with HIV and children 48", "WHO consolidated guidelines on tuberculosis: Fourth edition iv iv 2.3.1 Concurrent use of tests in people living with HIV 50 2.3.2 Concurrent use of tests in children without HIV or with unknown HIV status 57 2.3.3 Concurrent use of tests in children with HIV 66 2.4. Follow-on diagnostic tests for detection of additional drug-resistance after TB confirmation 71 2.4.1 Low complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents 71 2.4.2 First-line LPAs 83 2.4.3 Second-line LPAs 87 2.4.4 High complexity reverse hybridization-based NAATs for detection of pyrazinamide resistance 92 2.4.5 Targeted next-generation sequencing 100 2.5. References 119 3. Recommendations for diagnosis of TB infection 121 3.1. Mycobacterium tuberculosis antigen-based skin tests for the diagnosis of TB infection 121 3.2. TB skin tests and interferon gamma release assays for the diagnosis of TB infection 139 3.3. TB skin tests and interferon gamma release assays for the diagnosis of TB disease 142 3.4. References 147 Annex 1. Guideline development methods 149 Annex 2. Conflict of interest assessment for Guideline Development Group and External Review Group members 153 Annex 3. GDG members expertise, region, gender 163 Web Annexes 166 Web Annex A. Acknowledgements, List of studies included in systematic review, GRADE profiles, Evidence to decision tables https://doi.org/10.2471/B09340 Web Annex B. Systematic reviews https://doi.org/10.2471/B09341", "v Acknowledgements The recommendations and remarks in this policy guideline on tuberculosis (TB) are the result of the collaborative effort of professionals from a range of specialties. The World Health Organization (WHO) is grateful for their time and support. There were separate Guideline Development Groups (GDGs) for each of the guidelines that have been included in these consolidated guidelines. The acknowledgements provided immediately below are specific to WHO guidelines that are new in this edition. Acknowledgements for prior guidelines are summarized in Web Annex A. The production and writing of this document \u2013 WHO consolidated guidelines on tuberculosis. Module 3: Diagnosis \u2013 was coordinated by Alexei Korobitsyn and Patricia Hall-Eidson, with the support of Carl-Michael Nathanson, under the guidance of Matteo Zignol and the overall direction of Tereza Kasaeva, Director of the WHO Global Programme on Tuberculosis & Lung Health (WHO/GTB). Low complexity nucleic acid amplification testing for detection of TB and resistance to rifampicin Concurrent testing WHO steering committee The preparation of this section of the guidelines was overseen by Alexei Korobitsyn with input from Annabel Baddeley, Annemieke Brands, Dennis Falzon, Tereza Kasaeva, Cecily Miller, Carl- Michael Nathanson, Jasmine Solangon, Maria de los Angeles Vargas, Sabine Vercuijl, Kerri Viney, and Matteo Zignol (all from the WHO Global TB Programme); Ajay Rangaraj and Elena Vovc (from the WHO Global HIV Programme); Soudeh Ehsani (WHO Regional Office for Europe); and Amos Fadare (WHO Country Office for Nigeria). Guideline development group Kobto Koura (Co-Chair), International Union Against Tuberculosis and Lung Disease, Paris, France; Jeremiah Chakaya Muhwa, Respiratory Society of Kenya, Nairobi, Kenya; Chamreun Sok Choub, Patients Advocate, Pnom Penh, Cambodia; Daniela Cirillo, San Raffaele Scientific Institute, Milan, Italy; Keertan Dheda, University of Cape Town, Cape Town, South Africa; Katherine Fielding, London School of Hygiene and Tropical Medicine, London, United Kingdom of Great Britain and Northern Ireland; Rumina Hasan, Aga Khan University, Karachi, Pakistan; Sirinapha Jittimanee, NTP Thailand Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand; Katharina Kranzer, London School of Hygiene and Tropical Medicine, London, United Kingdom of Great Britain and Northern Ireland; Andrei Mariandyshev, Northern State Medical University, Ministry of Health of Russia, Arkhangelsk, Russian Federation; Norbert Ndjeka,", "WHO consolidated guidelines on tuberculosis: Fourth edition vi National TB Programme of South Africa, Pretoria, South Africa; Shaheed Vally Omar, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa; Hojoon Sohn, Seoul National University, Seoul, Republic of Korea, Thomas Shinnick, Consultant, Atlanta, USA; Sabira Tahseen, National Tuberculosis Control Programme, Ministry of National Health Services Regulations and Coordination, Government of Pakistan, Islamabad, Pakistan; Timothy Walker, University of Oxford, Ho Chi Minh City, Viet Nam; Xichao Ou, National Tuberculosis Control and Prevention Center, Chinese CDC; Beijing, China. External review group Martina Casenghi (Elizabeth Glaser Pediatric AIDS Foundation, Washington, USA), Jamilya Ismailova (National TB Program, Dushanbe, Tajikistan), Blessy Kumar (Global coalition of TB advocates, Delhi, India), Fernanda Dockhorn da Costa Johansen (National TB Program, Rio de Janeiro, Brazil), Petra de Haas (KNCV, The Hague, Netherlands), and Platon Eliseev (National Center of Phtisiopulmonology, Moscow, Russian Federation). Methodologist Lawrence Mbuagbaw, McMaster University, Hamilton, Canada Systematic review team Review of diagnostic accuracy: Johanna Ahsberg (University of Southern Denmark, Odense, Denmark), Stephanie Bjerrum (University of Southern Denmark, Odense, Denmark), David Horne (University of Washington, Seattle, USA), Leeberk Raja Inbaraj (ICMR-National Institute for Research in Tuberculosis, Chennai, India), Nazir Ismail (Wits University, Johannesburg, South Africa), Alexander Kay (Baylor College of Medicine, Houston, USA), Mikashmi Kohli (FIND, Geneva Switzerland), Maia Madison (Baylor College of Medicine, Houston, USA), Laura Olbrich (LMU Klinikum, Munich, Germany), Katie Scandrett (University of Birmingham, Birmingham, United Kingdom of Great Britain and Northern Ireland), Maunank Shah (John Hopkins University, Elkridge, USA), Yemisi Takwoingi (University of Birmingham, Birmingham, United Kingdom of Great Britain and Northern Ireland) Review of research into costs and cost effectiveness: Suvesh Shrestha and Alice Zwerling (University of Ottawa, Canada). Review of and research into user perspectives, feasibility, and acceptability: Nora Engel (University of Maastricht, Maastricht, Netherlands) and Eleanor Ochodo (Kenya Medical Research Institute, Kisumu, Kenya). Observers Grania Bridgen Global Fund to Fight AIDS, TB and Malaria, Geneva, Switzlerland; Smiljka de Lussigny, Unitaid, Geneva, Switzerland; Anisa Ghadrshenas, Unitaid, Geneva, Switzerland; Brian Kaiser, Global Drug Facility, Stop TB Partnership, Geneva, Switzerland; Melanie Kitongo, Global Fund to Fight AIDS, TB and Malaria, Geneva, Switzerland; Adam Penn-Nicholson, FIND, Geneva Switzerland; Morten Ruhwald, FIND, Geneva, Switzerland. Funding Funding from the Gates Foundation is gratefully acknowledged. The views of the funding agencies have not influenced the development and content of these guidelines.", "vii Abbreviations and acronyms AIDS acquired immunodeficiency syndrome AlereLAM Alere Determine TB LAM Ag aNAAT automated nucleic acid amplification test BAL bronchoalveolar lavage BCG bacille Calmette\u2013Gu\u00e9rin BD Becton Dickinson cfu colony forming units CI confidence interval CrI credible interval CRS composite reference standard CSF cerebrospinal fluid DALY disability-adjusted life year DIAMA Diagnostics for Multidrug Resistant Tuberculosis in Africa DNA deoxyribonucleic acid DR-TB drug-resistant tuberculosis DST drug susceptibility testing ERG External external review group FIND Foundation for Innovative New Diagnostics FL-LPA first-line line probe assay GDG guideline development group Global Fund Global Fund to Fight AIDS, Tuberculosis and Malaria GRADE Grading of Recommendations Assessment, Development and EvaluationHIV human immunodeficiency virus ICER incremental cost\u2013effectiveness ratio IGRA interferon-gamma release assay IVD in vitro diagnostic LAM lipoarabinomannan LAMP loop-mediated isothermal amplification LC-aNAAT low-complexity automated nucleic acid amplification test LC-mNAAT low-complexity manual nucleic acid amplification test LC-NAAT low-complexity nucleic acid amplification test LF-LAM lateral flow urine lipoarabinomannan assay LMIC low- and middle-income countries LPA line probe assay LSHTM London School of Hygiene & Tropical Medicine MC-aNAAT moderate-complexity automated nucleic acid amplification test MDR multidrug-resistant", "WHO consolidated guidelines on tuberculosis: Fourth edition viii MDR/RR-TB multidrug-resistant tuberculosis or rifampicin-resistant tuberculosis MDR-TB multidrug-resistant tuberculosis MRS microbiological reference standard Mtb Mycobacterium tuberculosis MTBC Mycobacterium tuberculosis complex mWRD molecular WHO-recommended rapid diagnostic test NAAT nucleic acid amplification test NAT nucleic acid test NGS next-generation sequencing NTP national tuberculosis programme PCR polymerase chain reaction PI prediction interval PICO population, intervention, comparator and outcome PQ prequalification PZA pyrazinamide QES quality evidence synthesis QUADAS quality assessment of diagnostic accuracy studies RIF rifampicin RNA ribonucleic acid RRDR rifampicin-resistance determining region RR-TB rifampicin-resistant tuberculosis SL-LPA second-line line probe assay SRL supranational TB reference laboratory SSM sputum smear microscopy STARD Standards for Reporting Diagnostic Accuracy Studies TB tuberculosis TBST Mtb antigen-based skin test TPT tuberculosis preventive treatment TST tuberculin skin test UN United Nations United Kingdom United Kingdom of Great Britain and Northern Ireland UR uncertainty range USA United States of America USAID United States Agency for International Development UV ultraviolet WGS whole genome sequencing WHO World Health Organization WHO/GTB Global Programme on Tuberculosis & Lung Health of the World Health Organization WRD WHO-recommended rapid diagnostic test WTP willingness-to-pay XDR extensively drug-resistant XDR-TB extensively drug-resistant tuberculosis", "ix Definitions Advanced HIV disease: for adults, adolescents, and children aged 5 years or more, \u201cadvanced HIV disease\u201d is defined as a CD4 cell count of less than 200 cells/mm3 or a WHO clinical stage 3 or 4 event at presentation for care. All children living with HIV aged under 5 years should be considered as having advanced disease at presentation. Age groups: the following definitions for adults and children are used in these guidelines for the purpose of implementing recommendations (countries may have other definitions under their national regulations): \u2022 an adult is a person aged 10 years and older; \u2022 a child is a person aged under 10 years. Grading of Recommendations Assessment, Development and Evaluation (GRADE): a system for rating quality of evidence and strength of recommendations; the GRADE approach is explicit, comprehensive, transparent and pragmatic, and is increasingly being adopted by organizations worldwide. HIV serious illness: HIV serious illness is defined based on any of the following symptoms: respiratory rate of \u2265 30/minute, temperature \u2265 39 \u00b0C, heart rate \u2265 120/minute, or unable to walk unaided. Inpatient health care setting: a health care facility where patients are admitted and assigned a bed while undergoing diagnosis and receiving treatment and care, for at least one overnight stay. Outpatient health care setting: a health care facility where patients are undergoing diagnosis and receiving treatment and care but are not admitted for an overnight stay (e.g. an ambulatory clinic or a dispensary).", "WHO consolidated guidelines on tuberculosis: Fourth edition x Executive summary It is estimated that about a quarter of the world\u2019s population is infected with Mycobacterium tuberculosis \u2013 the bacterium that causes tuberculosis (TB) disease. Testing for TB infection can identify individuals who would benefit the most from TB preventive treatment (TPT). However, despite the availability of preventive measures and disease treatment, TB remains a leading cause of death due to a single infectious agent. TB has probably replaced coronavirus disease (COVID-19) as the leading cause of death worldwide for the first time since the start of the global pandemic (1). In recognition of the need to end TB globally, the United Nations (UN) held the world\u2019s first high- level meeting on TB in 2018. The political declaration from the meeting included commitments by Member States to achieving four new global targets (2), which were subsequently renewed at the second UN high-level meeting in 2023. The commitments included two that relied on diagnosis of TB infection and disease: providing TPT to at least 45 million people between 2024 and 2027, and reaching 90% of the estimated number of people who develop TB with quality-assured diagnosis and treatment from 2023 to 2027 (2). These commitments align with the World Health Organization\u2019s (WHO\u2019s) End TB Strategy, which calls for the detection of individuals living with TB infection who are at higher risk of progression to active TB so that they can receive TPT, as well as the early diagnosis of TB and drug-resistant TB (DR-TB) through universal drug susceptibility testing (DST). These global commitments and plans highlight the critical role of TB testing for the rapid and accurate detection of TB infection, disease and drug resistance (3). To support countries in their efforts to strengthen detection of TB infection, disease and drug resistance, the WHO Global TB Programme issues evidence-based policy guidance on TB testing strategies and technologies; this guidance is routinely updated. Since the most recent consolidated guidelines on TB diagnosis were issued in 2024: \u2022 new evidence has become available on the use of WHO-recommended rapid diagnostic tests (WRDs) for the initial detection of TB and resistance to rifampicin among populations that are at increased risk of TB-related morbidity and mortality (e.g. people living with HIV and children); \u2022 a systematic assessment of evidence on molecular WRDs (mWRDs) previously recommended as individual products was completed to determine the placement of mWRDs", "within existing or new classes of TB diagnostic technologies; and \u2022 a call from countries was received to combine the policy guidance on TB infection, disease and drug-resistance testing into these consolidated guidelines on TB diagnosis, to streamline implementation of national testing programmes. In response, this document is being issued as the fourth edition of the consolidated guidelines on TB diagnosis. When compared with the third edition (issued in 2024), this guideline is the first to combine the WHO policy guidance on diagnosis of TB infection, disease and drug resistance into a single reference document; also, it establishes two new classes of TB diagnostic", "Executive summary xi technologies (for the initial detection of TB and resistance to rifampicin), and outlines new recommendations on concurrent testing of respiratory and non-respiratory samples among adults and adolescents with HIV, children with HIV, and children without HIV or with unknown HIV status. The main changes from the previous WHO guidelines are summarized in Box A. The set of 21 new and existing recommendations for diagnosis of TB infection, disease and DR-TB are presented in Table A. These recommendations supersede those presented in previous editions of the guidelines and are supported by updated operational guidance that is published as the fourth edition of the WHO operational handbook on tuberculosis. Module 3: diagnosis. The operational handbook includes further details on the individual tests that are recommended for use; the selection, introduction and implementation of tests for TB infection, diagnosis and drug resistance; and updated diagnostic algorithms that reflect the updates contained within these guidelines. \u00ce Two new classes of TB diagnostic tests for the initial detection of TB and resistance to rifampicin were established; these classes differ in the level of procedure and test result automation, and include tests that were previously recommended as standalone products. The new low-complexity automated nucleic acid amplification test (LC-aNAAT) class includes the Xpert\u00ae MTB/RIF and Xpert MTB/ RIF Ultra assays, and the Truenat \u00ae MTB Plus and MTB-RIF Dx assays. The low- complexity manual nucleic acid amplification test (LC-mNAAT) class includes the LoopampTM MTBC Detection Kit (TB LAMP) (Eiken Chemical). These new class- based recommendations supersede previous product-specific recommendations. \u00ce Concurrent testing of respiratory and non-respiratory samples for the initial detection of TB and resistance to rifampicin is newly recommended for adults and adolescents living with HIV, children living with HIV, and children without HIV or with unknown HIV status. \u00ce Existing guidelines on tests for TB infection were added, to consolidate policy guidance on testing for TB diagnosis, drug resistance and infection. \u00ce A description of TB diagnostic test determination and the pathways for TB diagnostic product prequalification by WHO was added to the Background section. \u00ce TB diagnostic test class description tables were revised to align with the class- determination criteria presented in the Background section. \u00ce The four prior web annexes covering systematic review and guideline development group (GDG) evidence to inform policy updates were consolidated into two web annexes. Web Annex A includes the systematic reviews, Grading of Recommendations Assessment,", "WHO consolidated guidelines on tuberculosis: Fourth edition xii Table A. Recommendations in the WHO consolidated guidelines on tuberculosis. Module 3: diagnosis, fourth edition 1. For adults and adolescents with signs or symptoms of TB or who screened positive1 for pulmonary TB, low-complexity automated NAATs should be used on respiratory samples as initial diagnostic tests for TB, rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence) 2. For people with bacteriologically confirmed TB2, low-complexity automated NAATs should be used on respiratory samples as initial tests for detection of resistance to rifampicin, rather than culture-based DST. (Strong recommendation, high certainty of evidence) 3. For people with signs and symptoms of TB meningitis, low-complexity automated NAATs on cerebral spinal fluid should be used for the initial diagnosis of TB meningitis, rather than smear microscopy or culture. (Strong recommendation, moderate certainty of evidence) 4. For people with signs and symptoms of extrapulmonary TB, low-complexity automated NAATs on lymph node tissue aspirate, pleural tissue, pleural fluid, synovial fluid, peritoneal fluid or pericardial fluid should be used for the initial diagnosis of TB, rather than smear microscopy or culture. (Strong recommendation, low certainty of evidence for synovial fluid and pericardial fluid; very low certainty of evidence for lymph node tissue aspirate, pleural tissue, pleural fluid and peritoneal fluid) 5. For people with signs and symptoms of pulmonary TB, moderate-complexity automated NAATs may be used on respiratory samples for the detection of pulmonary TB, and of rifampicin and isoniazid resistance, rather than culture and phenotypic DST. (Conditional recommendation, moderate certainty of evidence) 6. For adults and adolescents with signs or symptoms or who screen positive for pulmonary TB, low-complexity manual NAATs should be used on respiratory samples as initial diagnostic tests for TB, rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence) 1 Having a positive result of a test, examination or other procedure used to distinguish people with a high likelihood of having TB disease from people who are highly unlikely to have TB. At present, the following tests are WHO-recommended as the screening tests: chest radiography (chest X-ray; CXR) with or without computer-aided detection (CAD), C-reactive protein (CRP) in people living with HIV, and molecular WHO-recommended rapid diagnostic test for TB (mWRD) ( https://www.who. int/publications/i/item/9789240022676). 2 A bacteriologically confirmed TB case is one from whom a biological specimen is positive by smear microscopy, culture or WRD (such as Xpert", "Executive summary xiii 7. For adults and adolescents with HIV who have signs or symptoms of TB, screen positive for TB, are seriously ill or have advanced HIV disease, concurrent testing using low-complexity automated NAATs on respiratory samples and LF-LAM on urine should be used as the initial diagnostic strategy for diagnosing TB, rather than low- complexity automated NAATs on respiratory samples alone. (Strong recommendation, low certainty of evidence) 8. For children who are HIV-negative or have an unknown HIV status, who have signs or symptoms or screen positive for pulmonary TB, concurrent testing using low- complexity automated NAATs on respiratory and stool samples should be used as the initial diagnostic strategy for diagnosing TB, rather than low-complexity automated NAATs on respiratory or stool samples alone. (Strong recommendation, low certainty of evidence) 9. For children with HIV who have signs or symptoms or screen positive for pulmonary TB, concurrent testing using low-complexity automated NAATs on respiratory and stool samples and LF-LAM on urine may be used as the initial diagnostic strategy for diagnosing TB, rather than low-complexity automated NAATs on respiratory or stool samples alone. (Conditional recommendation, low certainty of evidence) 10. For people with bacteriologically confirmed pulmonary TB, low-complexity automated NAATs may be used on sputum for the initial detection of resistance to isoniazid and fluoroquinolones, rather than culture-based phenotypic DST. (Conditional recommendation, moderate certainty of evidence) 11. For people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low-complexity automated NAATs may be used on sputum for the initial detection of resistance to ethionamide, rather than DNA sequencing of the inhA promoter. (Conditional recommendation, very low certainty of evidence) 12. For people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low-complexity automated NAATs may be used on sputum for the initial detection of resistance to amikacin, rather than culture-based phenotypic DST. (Conditional recommendation, low certainty of evidence) 13. For people with a sputum smear-positive specimen or a cultured isolate of MTBC, commercial molecular LPAs may be used as the initial test instead of phenotypic culture-based DST to detect resistance to rifampicin and isoniazid. (Conditional recommendation, moderate certainty of evidence) 14. For people with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to fluoroquinolones. (Conditional recommendation, moderate certainty of evidence for test accuracy) NEW NEW NEW", "WHO consolidated guidelines on tuberculosis: Fourth edition xiv 15. For people with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to the SLIDs. (Conditional recommendation, low certainty of evidence for test accuracy) 16. For people with bacteriologically confirmed TB, high-complexity reverse hybridization- based NAATs may be used on Mtb culture isolates for detection of pyrazinamide resistance rather than culture-based phenotypic DST. (Conditional recommendation, very low certainty of evidence) 17. For people with bacteriologically confirmed pulmonary TB disease, targeted next- generation sequencing technologies may be used on respiratory samples to diagnose resistance to rifampicin, isoniazid, fluoroquinolones, pyrazinamide and ethambutol, rather than culture-based phenotypic DST. (Conditional recommendation, certainty of evidence moderate [isoniazid and pyrazinamide] and low [rifampicin, fluoroquinolones and ethambutol]) 18. For people with bacteriologically confirmed rifampicin-resistant pulmonary TB disease, targeted next-generation sequencing technologies may be used on respiratory samples to diagnose resistance to isoniazid, fluoroquinolones, bedaquiline, linezolid, clofazimine, pyrazinamide, ethambutol, amikacin and streptomycin, rather than culture-based phenotypic DST. (Conditional recommendation, certainty of evidence high [isoniazid, fluoroquinolones and pyrazinamide], moderate [ethambutol], low [bedaquiline, linezolid, clofazimine and streptomycin] and very low [amikacin]) 19. Mycobacterium tuberculosis antigen-based skin tests may be used to test for TB infection. (Conditional recommendation, very low certainty of evidence for test accuracy) 20. Either a tuberculin skin test or an interferon-gamma release assay can be used to test for TB infection. (Strong recommendation, very low certainty of evidence for test accuracy) 21. Interferon-gamma release assays (IGRAs) and tuberculin skin tests (TSTs) should not be used in low- and middle-income countries for the diagnosis of pulmonary or extrapulmonary TB or for the diagnostic work-up of adults (including people living with HIV) with suspected active TB. (Strong recommendation) DNA: deoxyribonucleic acid; DST: drug susceptibility testing; HIV: human immunodeficiency virus; LF-LAM: lateral flow urine lipoarabinomannan assay; LPA: line probe assay; MDR/RR-TB: multidrug-resistant or rifampicin-resistant TB; Mtb: Mycobacterium tuberculosis; MTBC: Mycobacterium tuberculosis complex; NAAT: nucleic acid amplification test; NGS: next-generation sequencing; SL-LPA: second-line line probe assay; SLID: second-line injectable drug; TB: tuberculosis; WHO: World Health Organization.", "1 1. Introduction 1.1. Background It is estimated that about a quarter of the world\u2019s population is infected with Mycobacterium tuberculosis (Mtb) \u2013 the bacterium that causes tuberculosis (TB) disease. Testing for TB infection can identify individuals who would benefit the most from TB preventive treatment (TPT). Without TPT, it is estimated that about 5\u201310% of people who are infected will develop TB disease over the course of their lives, usually within 5 years of the initial infection (1). Despite the availability of preventive measures and disease treatment, TB remains a leading cause of death due to a single infectious agent, and has probably replaced coronavirus disease (COVID-19) as the leading cause of death worldwide for the first time since the start of the global pandemic (1). In 2023, it is estimated that 10.8 million people fell ill with TB, but only 8.2 million were diagnosed. In addition, resistance to the antibiotics that are used to treat TB remains a challenge, with an estimated 400 000 people (95% uncertainty interval [UI]: 370 000\u2013450 000) having developed either rifampicin-resistant TB (RR-TB), or TB resistant to both rifampicin and isoniazid, defined as multidrug-resistant TB (MDR-TB). In 2018, the United Nations (UN) held the world\u2019s first high-level meeting on TB. The political declaration from the meeting included commitments by Member States to achieve four new global targets (2). These commitments were subsequently renewed at the second UN high- level meeting in 2023; they included provision of TPT to at least 45 million people between 2024 and 2027, and reaching 90% of the estimated number of people who develop TB with quality-assured diagnosis and treatment from 2023 to 2027 (3). In addition, the World Health Organization\u2019s (WHO\u2019s) End TB Strategy calls for the detection of individuals living with TB infection who are at higher risk of progression to active TB so that they can receive TPT, as well as the early diagnosis of TB and universal drug susceptibility testing (DST). These global commitments and plans highlight the critical role of TB testing for the rapid and accurate detection of TB infection, disease and drug resistance (4). Over recent years, the WHO Global TB Programme (WHO/GTB) has issued evidence-based policy guidance on diagnostic testing, to support countries in their efforts to detect TB infection, disease and drug resistance. When novel diagnostic tools are developed and evidence on their use and impact becomes available, WHO/GTB commissions", "WHO consolidated guidelines on tuberculosis: Fourth edition 2 This document is the fourth edition of WHO policy guidelines on TB diagnosis. Compared with the third edition, issued in 2024, this document: \u2022 is the first to combine guidance on diagnosis of TB infection, disease and drug resistance into a single reference document; \u2022 establishes two new classes of TB diagnostic technologies (for the initial detection of TB and resistance to rifampicin), which include tests previously recommended for use as individual products; and \u2022 outlines new recommendations on concurrent testing of respiratory and non-respiratory samples among adults and adolescents with HIV, children with HIV, and children without HIV or with unknown HIV status. 1.2. WHO TB diagnostic class determination and product prequalification Over the past 16 years, WHO has endorsed a range of diagnostic technologies (Table 1.1.1). The WHO assessment process for TB diagnostics has recently evolved to focus on evaluating classes of TB diagnostic technologies rather than specific products. Class determination is managed by WHO/GTB for new diagnostic testing technologies, and it includes an evaluation of the following characteristics: \u2022 purpose of use (i.e. detection of TB or drug-specific resistance); \u2022 principle of action; \u2022 infrastructure and human resource requirements; \u2022 complexity of the testing procedure and associated instrumentation; \u2022 reporting method (automated versus manual); and \u2022 intended setting of use (e.g. reference or peripheral low-complexity, near point-of-care). These characteristics are compared between the new technology and each of the existing classes already recommended by WHO. When characteristics differ from existing classes, the new technology will undergo an evidence review as \u201cfirst-in-class\u201d via Pathway A (described below). When characteristics match those of an existing class, the new technology will undergo a \u201cwithin-class\u201d assessment (Pathway B below). 1.2.1 Pathway A New technologies will require a Pathway A review if they differ from technologies in existing classes in terms of the characteristics listed above. Evidence synthesis and review and development of recommendations will be conducted through the established WHO/ GTB guideline development process using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. If recommended by a GDG after evidence review, technologies will be referred for WHO prequalification assessment (as available). If a prequalification assessment procedure is not available, the WHO/GTB recommendation will stand until the prequalification procedure becomes available and is successfully completed.", "1. Introduction 3 1.2.2 Pathway B Technologies will require a Pathway B review if they share characteristics with an existing class and are therefore not first-in-class. Review of these within-class technologies depends on availability of a prequalification assessment procedure for the class: \u2022 If a prequalification assessment procedure is available, manufacturers may proceed directly with assessment. \u2022 If a prequalification assessment procedure is not yet available, an evidence review will be conducted through a WHO/GTB evidence assessment process, facilitated by the Technical Advisory Group on TB Diagnostics and Laboratory Strengthening. If recommended by WHO/GTB, the technology will be added to the relevant class in the latest policy guidance. The recommendation will stand until the prequalification assessment procedure becomes available and is successfully completed. 1.3. Testing classes and products As highlighted above, all technologies with a WHO/GTB recommendation are expected to undergo prequalification assessment, as available. Successful assessment will be required to maintain a WHO/GTB recommendation. The current set of TB diagnostic testing classes and included products are listed in Table 1.1.1, and the two new classes are discussed below. Table 1.1.1. Classes and products of TB tests for detection of TB, drug-resistant TB and TB infection included in the current guidelines Technology class Included products Initial tests for TB diagnosis with drug-resistance detection NEW: Low-complexity automated nucleic acid amplification tests (NAATs) for detection of TB and resistance to rifampicin Xpert\u00ae MTB/RIF and Xpert MTB/RIF Ultra (Cepheid) Truenat\u00ae MTB Plus and Truenat MTB-RIF Dx (Molbio) Moderate-complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid Abbott RealTime\u00ae MTB and Abbott RealTime MTB RIF/INH (Abbott) BD MAX\u2122 MDR-TB (Becton Dickinson) cobas\u00ae MTB and cobas MTB-RIF/INH (Roche) FluoroType\u00ae MTB and FluoroType MTBDR (Hain Lifescience/Bruker) Initial tests for TB diagnosis without drug-resistance detection NEW: Low-complexity manual NAATs for detection of TB LoopampTM MTBC Detection Kit (TB LAMP) (Eiken Chemical) Antigen detection in a lateral flow format (biomarker-based detection) (LF-LAM) for detection of TB Determine\u2122 TB LAM Ag (Alere/Abbott)", "WHO consolidated guidelines on tuberculosis: Fourth edition 4 Technology class Included products Follow-on tests for detection of TB drug resistance Low-complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents Xpert\u00ae MTB/XDR (Cepheid) Line probe assays (LPAs) for detection of TB drug resistance GenoType\u00ae MTBDRplus v1 and v2; and GenoType MTBDRsl (Hain Lifescience/Bruker) Genoscholar\u2122 NTM+MDRTB II and Genoscholar PZA-TB II (Nipro) Targeted next-generation sequencing (NGS) tests for detection of TB drug resistance Deeplex\u00ae Myc-TB (GenoScreen/Illumina) AmPORE-TB\u00ae (Oxford Nanopore Technologies) TBseq\u00ae (Shengting Medical Technology Company) Tests for TB infection Mycobacterium tuberculosis antigen-based skin tests (TBSTs) Diaskintest\u00ae (Generium) Siiltibcy\u2122 (Serum Institute of India) C-TST (Anhui Zhifei Longcom) Interferon-gamma release assays (IGRAs) T-SPOT.TB (T-Spot) (Revvity) TB-IGRA (Wantai BioPharm) QuantiFERON-TB Gold Plus (QFT-Plus) (QIAGEN) STANDARD E TB-Feron ELISA (SD BIOSENSOR)3 LIAISON QFT-Plus CLIA (Diasorin)3 Tuberculin skin tests Tuberculin purified protein derivative (PPD) products NAAT: nucleic acid amplification test; TB: tuberculosis. 1.3.1 Initial tests for TB diagnosis with drug resistance detection Low-complexity automated nucleic acid amplification tests (NAATs) for detection of TB and resistance to rifampicin The low-complexity automated nucleic acid amplification tests (LC-aNAATs) include tools such as Xpert\u00ae MTB/RIF Ultra (Cepheid) and Truenat\u00ae MTB Plus with MTB-RIF Dx (Molbio). These tests provide largely automated solutions suitable for decentralized laboratories, and are currently the most widely used tests for the initial detection of TB and resistance to rifampicin. The testing instruments use software and hardware (computers) to report results, and they require well- established laboratory networks and trained personnel. 3 For WHO statement and evidence assessment on new IGRAs see WHO operational handbook on tuberculosis. Module 3: diagnosis.", "1. Introduction 5 Moderate-complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid The moderate-complexity automated NAATs (MC-aNAATs) are faster and less complex to perform than phenotypic culture-based DST and line probe assays (LPAs), and are largely automated after the sample preparation step. They may be used as an initial test for simultaneous detection of TB and resistance to rifampicin and isoniazid. This type of NAAT offers the potential for rapid provision of accurate results and for testing efficiency where high volumes of tests are required daily. Hence, they are suited to areas with a high population density and rapid sample referral systems. 1.3.2 Initial tests for TB diagnosis without drug resistance detection Low-complexity manual NAATs The low-complexity manual NAAT (LC-mNAAT), loop-mediated isothermal amplification (LAMP), is based on DNA amplification at a single temperature range; this contrasts with the polymerase chain reaction (PCR), which requires a thermocycler. Detection of amplified product is done visually, using an ultraviolet (UV) lamp, directly in the reaction tubes. The method requires only basic equipment and can be implemented at the lowest levels of the laboratory network. However, detection of mutations in resistance-associated genes is not available with the currently recommended technology. Antigen detection in a lateral flow format (biomarker-based detection) The currently available lateral flow urine lipoarabinomannan assay (LF-LAM) has suboptimal sensitivity and specificity; thus, it is not suitable as a diagnostic test for TB in all populations. However, in contrast to traditional diagnostic methods, the urine LF-LAM assay demonstrates improved sensitivity for the diagnosis of TB among individuals coinfected with HIV. 1.3.3 Follow-on tests for detection of TB drug resistance Low-complexity automated NAATs for the detection of resistance to isoniazid and second-line anti-TB agents The LC-aNAATs are recommended for use as a reflex test in specimens determined to be positive for Mtb complex (MTBC); these tests offer rapid DST in intermediate and peripheral laboratories. The first product in this class simultaneously detects resistance to isoniazid, fluoroquinolones, ethionamide and amikacin. Results are available in under 90 minutes; this is faster than with the current standard of care, which includes LPAs and culture-based phenotypic DST. Line probe assays LPAs are a family of DNA strip-based tests that can detect the MTBC DNA and determine its drug-resistance profile. The tests do this through the pattern of binding of amplicons (DNA amplification products) to probes that target specific parts of the MTBC genome; that", "WHO consolidated guidelines on tuberculosis: Fourth edition 6 agents, and they provide mutation-specific data for common variants. Testing platforms have been designed for a reference laboratory setting and are most applicable to high TB burden countries. Results can be obtained in 5 hours (5). Targeted next-generation sequencing tests Tests based on targeted next-generation sequencing (NGS) are used for follow-on detection of resistance to a broad range of anti-TB drugs after the initial detection of TB or of rifampicin resistance. This class of tests is based on technology that combines amplification of selected genes with NGS to detect resistance to many drugs with a single test. Because targeted NGS can interrogate entire genes to identify specific mutations associated with resistance, the accuracy may be better than that of existing WHO-recommended rapid diagnostic tests (WRDs). In addition, new tests based on targeted NGS can detect resistance to new and repurposed drugs that are not currently included in any other molecular assays. Hence, this class of tests offers great potential to provide comprehensive resistance detection matched to modern treatment regimens. 1.3.4 Tests for TB infection Mtb antigen-based skin tests Mtb antigen-based skin tests (TBSTs) are used for the indirect detection of TB infection. TBSTs rely on intradermal injection of Mtb-specific antigens; the antigens elicit a localized skin reaction in infected individuals that is detected by measurement of a local induration 48\u201372 hours after administration. Although these tests continue to rely on patient injection and return visits for result interpretation, they are more specific than the WHO-recommended tuberculin skin tests (TSTs). Interferon-gamma release assays Interferon-gamma release assays (IGRAs) are in vitro blood-based tests that are used to indirectly test for TB infection. They do this by measuring either the amount of interferon-gamma that is released by lymphocytes in whole blood after exposure to Mtb-specific antigens or the number of T-lymphocytes within the whole blood that produce interferon-gamma. IGRA testing requires days to perform owing to the blood incubation steps and it can be challenging to perform among patients for whom phlebotomy can be difficult (e.g. children); however, this is the only type of test for TB infection in which the results are not affected by prior bacille Calmette\u2013 Gu\u00e9rin (BCG) vaccination for TB. Hence, IGRAs are a promising alternative for detection of TB infection in settings with high rates of BCG vaccination. Tuberculin skin tests TSTs were the first class of tests to be", "recommended for detection of TB infection; they rely on intradermal injection of a mix of antigens to Mtb, non-tuberculous mycobacteria and the BCG vaccine formulation, followed by detection of a localized skin induration-based response after 48\u201372 hours. As with the TBSTs, these tests can facilitate TB infection testing in children and other patients for whom phlebotomy is challenging, but they may also produce false positive results in people infected with mycobacteria other than TB and in those who are BCG vaccinated.", "1. Introduction 7 Regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of new diagnostic tests. 1.4. Scope of the document This document provides background, justification and recommendations for novel diagnostic tools for detecting MTBC, the presence or absence of mutations in target genes proven to be associated with anti-TB drug resistance, and TB infection. 1.5. Target audience The target audience for these guidelines includes laboratory managers, clinicians and other health care staff, HIV and TB programme managers, policy-makers, technical agencies, donors and implementing partners supporting the use of TB diagnostic tests in resource-limited settings. The document may also be of use to individuals responsible for programme planning, budgeting, mobilizing resources and implementing training activities for the programmatic management of drug-resistant TB (DR-TB). 1.6. Scope of the document This document provides background, justification and recommendations on novel diagnostic tools for detecting MTBC, the presence or absence of mutations in target genes proven to be associated with anti-TB drug resistance, and TB infection. 1.7. Target audience The target audience for these guidelines includes laboratory managers, clinicians and other health care staff, HIV and TB programme managers, policymakers, technical agencies, donors and implementing partners supporting the use of TB diagnostics in resource-limited settings. Individuals responsible for programme planning, budgeting, mobilizing resources and implementing training activities for the programmatic management of DR-TB may also find this document useful.", "9 2. Recommendations for diagnosis of TB disease 2.1. Initial diagnostic tests for diagnosis of TB with drug-resistance detection 2.1.1 LC-aNAATs for detection of TB and resistance to rifampicin Rapid detection of TB and rifampicin resistance is a critical global priority. Over a decade ago, the first recommendation on molecular testing for the diagnosis of TB and detection of resistance significantly transformed the TB diagnostic landscape. These technologies have proven highly accurate compared with smear microscopy, and they can detect rifampicin resistance rapidly. They do not require highly skilled individuals or designated molecular laboratory infrastructure for testing. In addition, they are largely automated after sample loading, up to the final report generation. These features make this class of low-complexity automated tests appealing for use in low- and middle-income countries (LMIC). Uptake of these technologies has been slowed by barriers related to costs, the supply chain, equipment maintenance and technical support. The lack of a healthy competitive environment has also been a contributory factor. The WHO Prequalification (PQ) programme for TB in vitro diagnostics (IVDs) has opened a pathway to allow more products to come to market and ensure quality. The current guidelines facilitated this process with the introduction of class- based recommendations for low-complexity NAATs. WHO PQ assessment progress for all low-complexity NAATs is reported on the WHO PQ website.4 4 In Vitro Diagnostics Under Assessment | WHO \u2013 Prequalification of Medical Products (IVDs, Medicines, Vaccines and Immunization Devices, Vector Control). NEW", "WHO consolidated guidelines on tuberculosis: Fourth edition 10 Diagnostic class description The features shown in Table 2.1.1.1 define the class of LC-aNAATs.: Table 2.1.1.1 Class criteria for LC-aNAATs Purpose Detection of TB and rifampicin resistance Principle of action Nucleic acid amplification testing Complexity Reagents Most reagents are enclosed in a disposable sealed container to which a clinical specimen is added. The disposable sealed container does not have special storage requirements Skills Basic technical skills (e.g. basic pipetting, precision not critical) Pipetting Either no, or only one, pipetting step in the process Testing procedure y May require an initial manual specimen treatment step before transferring the specimen into the disposable sealed container for automated processing y Automated DNA extraction y Automated real-time PCR y Results generation Type of test result reporting Automated Setting of use Basic laboratory (no special infrastructure needed) DNA: deoxyribonucleic acid; LC-aNAAT: low-complexity automated nucleic acid amplification test; PCR: polymerase chain reaction; TB: tuberculosis. The products for which eligible data met the class-based performance criteria for LC-aNAATs were: \u2022 Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]) \u2013 for pulmonary TB, extrapulmonary TB and resistance to rifampicin; and \u2022 Truenat MTB Plus and Truenat MTB-RIF Dx (Molbio, Goa, India) \u2013 for pulmonary TB and resistance to rifampicin. Data on Truenat MTB Plus and MTB-RIF Dx were more limited than those for Xpert Ultra. Regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of these diagnostic tests. Extrapolation to other brand-specific tests cannot be made, and any new in-class technologies, or new indications for technologies currently included in the class, will need to be evaluated by WHO PQ and WHO/GTB, respectively. The publication WHO operational handbook on tuberculosis. Module 3: Diagnosis describes the tests included in this class.", "2. Recommendations for diagnosis of TB disease 11 Recommendations 1. For adults and adolescents with signs or symptoms of TB or who screened positive for pulmonary TB, low-complexity automated NAATs should be used on respiratory samples as initial diagnostic tests for TB rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence) Remarks \u2022 For adults, respiratory samples include sputum (expectorated or induced), tracheal aspirate or bronchoalveolar lavage (BAL). \u2022 The term \u201cperson screened positive\u201d refers to a person in whom a screening test has yielded a positive result.5 \u2022 Children and specifically children living with HIV are discussed in the section on the concurrent use of initial TB diagnostic tests in children. \u2022 Adults and adolescents living with HIV are discussed in the section on the concurrent use of initial TB diagnostic tests in people living with HIV. \u2022 The products for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation were Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]) and Truenat MTB Plus (Molbio, Goa, India). Data on Truenat MTB Plus and MTB-RIF Dx were more limited than those for Xpert Ultra. 2. For people with bacteriologically confirmed TB, low-complexity automated NAATs should be used on respiratory samples as initial tests for detection of resistance to rifampicin rather than culture-based DST. (Strong recommendation, high certainty of evidence) Remarks \u2022 This recommendation applies to all people living with HIV. \u2022 The recommendation was extrapolated to children based on the generalization of data from adults and limited data from children. For children, respiratory samples include sputum, BAL, induced sputum, nasopharyngeal aspirate and gastric aspirate. \u2022 The recommendation was extrapolated to people with extrapulmonary TB based on the generalization of data from adults with pulmonary TB. \u2022 The products for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation were Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]) and Truenat MTB-RIF Dx (Molbio, Goa, India). Data on MTB-RIF Dx were more limited than those for Xpert Ultra. 5 Having a positive result of a test, examination or other procedure used to distinguish people with a high likelihood of having TB disease from people who are highly unlikely to have TB. At present, the following tests are WHO-recommended as the screening tests: chest radiography (chest X-ray; CXR) with or without computer-aided detection (CAD), C-reactive protein (CRP) in people", "WHO consolidated guidelines on tuberculosis: Fourth edition 12 3. For people with signs and symptoms of TB meningitis, low-complexity automated NAATs on cerebral spinal fluid should be used for the initial diagnosis of TB meningitis rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence) Remarks \u2022 This recommendation applies to all people with signs and symptoms of TB meningitis, including people living with HIV and children. \u2022 Where possible, culture may be performed in addition to automated NAAT testing, to maximize the opportunity for diagnosis and detection of DR-TB. \u2022 The product for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation was Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]). Data on Truenat MTB Plus and MTB-RIF Dx were limited and variable and thus were insufficient for evaluation. 4. For people with signs and symptoms of extrapulmonary TB, low-complexity automated NAATs on lymph node tissue aspirate, pleural tissue, pleural fluid, synovial fluid, peritoneal fluid or pericardial fluid should be used for the initial diagnosis of TB rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence) Remarks \u2022 This recommendation applies to all people with signs and symptoms of the respective form of extrapulmonary TB, including people living with HIV and children. \u2022 Data on the performance of LC-aNAATs when used with urine and blood samples were limited or inconsistent. \u2022 Where possible, culture may be performed in addition to automated NAAT testing, to maximize the opportunity for diagnosis and detection of DR-TB. \u2022 The product for which eligible data met the class-based performance criteria for LC-aNAATs for this recommendation was Xpert MTB/RIF Ultra (Cepheid, Sunnyvale, United States of America [USA]). Data on Truenat MTB Plus and MTB-RIF Dx were limited and variable and thus were insufficient for evaluation. Justification and evidence WHO/GTB initiated an update of the previous guidelines and commissioned a systematic review on the use of LC-aNAATs (Xpert Ultra, Truenat MTB Plus and Truenat MTB-RIF Dx assays) for the diagnosis of TB and resistance to rifampicin in people with signs and symptoms of TB, or who screened positive for TB. The data on the performance of LC-aNAATs alone in these populations, compared with smear microscopy and culture, are presented in Web Annexes B.1\u2013B.4. Recommendations on concurrent testing for children and people living with HIV supersede the use of LC-aNAATs alone in these populations (see Section", "2. Recommendations for diagnosis of TB disease 13 Detection of pulmonary TB Should LC-aNAATs on respiratory samples be used to diagnose pulmonary TB in adults and adolescents with signs and symptoms or who screened positive for pulmonary TB, against a microbiological reference standard? Thirty-five studies (14 845 participants) assessed diagnostic accuracy using sputum specimens and comparing with a microbiological reference standard (MRS); however, one of those studies had no people with TB (Zar 2019) and so sensitivity was not estimable. The sensitivities in the remaining 34 studies (14 840 participants) included in the meta-analysis were between 54% and 100%, and the specificities were between 71% and 100% (Fig. 2.1.1). The summary sensitivity was 90.4% (95% confidence interval [CI]: 88.0\u201392.4), and the summary specificity was 94.9% (95% CI: 93.0\u201396.3). The certainty of evidence for sensitivity and specificity was graded as \u201chigh\u201d. For more details, see Web Annex B.1. Fig. 2.1.1. Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in sputum samples and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by assay and author. Study Jose 2024 Ngangue 2022 Penn-Nicholson 2021 Theron 2024 Aguilera-Alonso 2022 Berhanu 2018 Boyles 2020 Calderwood 2023 Chakravorty 2017 Chien 2020 Chilukutu 2022 Dorman 2018 Jaganath 2021 Li 2023 Liu 2021 MacLean 2023 Mishra 2020a Mishra 2020b Moodley 2022 Mukoka 2023 Opota 2019 Park 2019 Pereira 2020 Piersimoni 2019 Saavedra 2021 Sabi 2018 Sabi 2022 Sava 2023 Sessolo 2023 Ssengooba 2020 Ssengooba 2024 Wang 2019 Wang 2022 Zar 2019 Zhang 2021 TP 18 224 295 131 2 50 62 223 175 10 76 408 5 96 3 77 62 38 59 7 45 19 23 116 149 4 13 270 103 1 66 102 322 0 24 FP 3 35 51 11 0 8 1 37 1 8 39 43 3 21 0 13 18 38 13 17 5 1 10 3 52 1 4 20 7 0 18 112 102 0 6 FN 1 10 51 20 1 6 13 24 25 6 16 54 1 4 0 2 10 6 11 6 2 2 0 7 8 1 4 14 5 0 5 15 27 0 1 TN 181 676 1144 222 2 173 131 612 76 141 608 934 12 247 4 498 149 86", "706 289 144 260 147 140 1210 33 61 426 62 5 160 269 627 5 68 Brand Truenat MTB Plus Truenat MTB Plus Truenat MTB Plus Truenat MTB Plus Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Sensitivity (95% CI) 0.95 [0.74, 1.00] 0.96 [0.92, 0.98] 0.85 [0.81, 0.89] 0.87 [0.80, 0.92] 0.67 [0.09, 0.99] 0.89 [0.78, 0.96] 0.83 [0.72, 0.90] 0.90 [0.86, 0.94] 0.88 [0.82, 0.92] 0.63 [0.35, 0.85] 0.83 [0.73, 0.90] 0.88 [0.85, 0.91] 0.83 [0.36, 1.00] 0.96 [0.90, 0.99] 1.00 [0.29, 1.00] 0.97 [0.91, 1.00] 0.86 [0.76, 0.93] 0.86 [0.73, 0.95] 0.84 [0.74, 0.92] 0.54 [0.25, 0.81] 0.96 [0.85, 0.99] 0.90 [0.70, 0.99] 1.00 [0.85, 1.00] 0.94 [0.89, 0.98] 0.95 [0.90, 0.98] 0.80 [0.28, 0.99] 0.76 [0.50, 0.93] 0.95 [0.92, 0.97] 0.95 [0.90, 0.98] 1.00 [0.03, 1.00] 0.93 [0.84, 0.98] 0.87 [0.80, 0.93] 0.92 [0.89, 0.95] Not estimable 0.96 [0.80, 1.00] Specificity (95% CI) 0.98 [0.95, 1.00] 0.95 [0.93, 0.97] 0.96 [0.94, 0.97] 0.95 [0.92, 0.98] 1.00 [0.16, 1.00] 0.96 [0.91, 0.98] 0.99 [0.96, 1.00] 0.94 [0.92, 0.96] 0.99 [0.93, 1.00] 0.95 [0.90, 0.98] 0.94 [0.92, 0.96] 0.96 [0.94, 0.97] 0.80 [0.52, 0.96] 0.92 [0.88, 0.95] 1.00 [0.40, 1.00] 0.97 [0.96, 0.99] 0.89 [0.84, 0.93] 0.69 [0.60, 0.77] 0.98 [0.97, 0.99] 0.94 [0.91, 0.97] 0.97 [0.92, 0.99] 1.00 [0.98, 1.00] 0.94 [0.89, 0.97] 0.98 [0.94, 1.00] 0.96 [0.95, 0.97] 0.97 [0.85, 1.00] 0.94 [0.85, 0.98] 0.96 [0.93, 0.97] 0.90 [0.80, 0.96] 1.00 [0.48, 1.00] 0.90 [0.84, 0.94] 0.71 [0.66, 0.75] 0.86 [0.83, 0.88] 1.00 [0.48, 1.00] 0.92 [0.83, 0.97] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 14 Detection of rifampicin resistance Should LC-aNAATs on respiratory samples be used to diagnose rifampicin resistance in adults and adolescents with signs and symptoms or who screened positive for pulmonary TB, against an MRS? Of the 13 studies (2553 participants) that evaluated sputum specimens, sensitivity for detecting rifampicin resistance was not estimable for two studies ( Fig. 2.1.2 ). The sensitivities in the remaining 11 studies (2540 participants) included in the meta-analysis were between 53% and 100%, and the specificities were between 97% and 100%. The summary sensitivity was 95.1% (95% CI: 83.1\u201398.7), and the summary specificity was 98.1% (95% CI: 97.0\u201398.7). Only two of the 11 included studies assessed Truenat MTB-RIF Dx; one of them, a study from a single country, had a sensitivity outside of confidence interval limits (53%). Nevertheless, overall, the certainty of evidence for both sensitivity and specificity was considered high. Fig. 2.1.2. Forest plot of LC-aNAAT sensitivity and specificity for detection of rifampicin resistance in respiratory specimens and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TN: true negative; TP: true positive. a Studies are sorted by assay and author. Detection of TB meningitis Should LC-aNAATs on cerebrospinal fluid (CSF) be used to diagnose TB meningitis in adults with signs and symptoms of TB meningitis, against an MRS? LC-aNAAT summary sensitivity and specificity were 88.2% (95% CI: 83.7\u201391.6) and 96.0% (95% CI: 86.8\u201398.9), respectively, based on 16 Xpert Ultra studies (1684 participants); the certainty of evidence was high for sensitivity and moderate for specificity (Fig. 2.1.3). Only data on Xpert Ultra were included in the evaluation to answer this population, intervention, comparator and outcome (PICO) question. Of note, trace results from Xpert Ultra were considered positive and formed a significant proportion of positive results (16\u201363%). Data on Truenat were limited and variable and thus were not included. For more details, see Web Annex B.3. Study Gomathi 2020 Penn-Nicholson 2021 Aguilera-Alonso 2022 Berhanu 2018 Chakravorty 2017 Chien 2020 Dorman 2018 Li 2023 MacLean 2023 Park 2019 Piersimoni 2019 Wang 2019 Wang 2022 TP 31 44 0 2 38 0 166 8 4 1 2 16 123 FP 17 9 0 1 2 0 6 0 2 0 0 0 10 FN 28 8 0 0 3 0 9 0 0 0 0 0 4 TN 558", "271 3 54 96 10 370 79 66 20 105 74 313 Brand Truenat MTB-RIF Dx Truenat MTB-RIF Dx Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Sensitivity (95% CI) 0.53 [0.39, 0.66] 0.85 [0.72, 0.93] Not estimable 1.00 [0.16, 1.00] 0.93 [0.80, 0.98] Not estimable 0.95 [0.90, 0.98] 1.00 [0.63, 1.00] 1.00 [0.40, 1.00] 1.00 [0.03, 1.00] 1.00 [0.16, 1.00] 1.00 [0.79, 1.00] 0.97 [0.92, 0.99] Specificity (95% CI) 0.97 [0.95, 0.98] 0.97 [0.94, 0.99] 1.00 [0.29, 1.00] 0.98 [0.90, 1.00] 0.98 [0.93, 1.00] 1.00 [0.69, 1.00] 0.98 [0.97, 0.99] 1.00 [0.95, 1.00] 0.97 [0.90, 1.00] 1.00 [0.83, 1.00] 1.00 [0.97, 1.00] 1.00 [0.95, 1.00] 0.97 [0.94, 0.99] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "2. Recommendations for diagnosis of TB disease 15 Fig. 2.1.3. Forest plot of LC-aNAAT sensitivity and specificity for detection of TB meningitis in cerebrospinal fluid and MRSa CI: confidence interval; CSF: cerebrospinal fluid; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. Detection of extrapulmonary TB Should LC-aNAATs on lymph node fluid be used to diagnose lymph node TB in adults and adolescents with signs and symptoms of lymph node TB, against an MRS? LC-aNAAT summary sensitivity and specificity from nine Xpert Ultra studies (445 participants) to diagnose lymph node TB in lymph node fluid in adults and adolescents with signs and symptoms of lymph node TB (Fig. 2.1.4) were 85.3% (95% CI: 73.4\u201392.4) and 74.1% (95% CI: 63.5\u201382.5), respectively. The certainty of evidence was low for sensitivity and very low for specificity. Only data on Xpert Ultra were included in the evaluation to answer this PICO question. The diagnostic accuracy of LC-aNAATs against a composite reference standard (CRS) that comprised the MRS plus patients who received clinical diagnoses (but were bacteriologically unconfirmed) was also considered. The use of the CRS markedly increased specificity to 97.4% (95% CI: 82.2\u201399.7) but decreased sensitivity to 71.3% (95% CI: 64.3\u201377.4), highlighting the known challenges with culture-based confirmation of TB with this sample type (see Web Annex B.3). Data on Truenat were limited and thus were not included. Study Mekkaoui 2021 Osei 2019 Perez-Risco 2018 Spencer-Gomes 2021 Sharma 2020 Sharma 2021 Donovan 2020 Bahr 2017 Cresswell 2020 Quinn 2021 Wang 2019 Yadav 2023 Huang 2021 Chin 2019 Penata 2021 Ninan 2022 Slail 2023 Shao 2020 TP 0 0 3 1 54 35 20 9 24 13 19 43 6 4 12 3 6 2 FP 2 0 0 0 0 38 4 12 15 4 0 0 19 3 8 0 1 26 FN 0 0 0 0 2 3 2 1 3 2 3 7 1 1 3 1 2 2 TN 49 6 1 49 188 40 62 107 162 29 17 250 58 3 181 37 29 54 Sensitivity (95% CI) Not estimable Not estimable 1.00 [0.29, 1.00] 1.00 [0.03, 1.00] 0.96 [0.88, 1.00] 0.92 [0.79, 0.98] 0.91 [0.71, 0.99] 0.90 [0.55, 1.00] 0.89 [0.71, 0.98] 0.87 [0.60, 0.98] 0.86 [0.65, 0.97] 0.86 [0.73, 0.94] 0.86 [0.42, 1.00]", "0.80 [0.28, 0.99] 0.80 [0.52, 0.96] 0.75 [0.19, 0.99] 0.75 [0.35, 0.97] 0.50 [0.07, 0.93] Specificity (95% CI) 0.96 [0.87, 1.00] 1.00 [0.54, 1.00] 1.00 [0.03, 1.00] 1.00 [0.93, 1.00] 1.00 [0.98, 1.00] 0.51 [0.40, 0.63] 0.94 [0.85, 0.98] 0.90 [0.83, 0.95] 0.92 [0.86, 0.95] 0.88 [0.72, 0.97] 1.00 [0.80, 1.00] 1.00 [0.99, 1.00] 0.75 [0.64, 0.84] 0.50 [0.12, 0.88] 0.96 [0.92, 0.98] 1.00 [0.91, 1.00] 0.97 [0.83, 1.00] 0.68 [0.56, 0.78] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 16 Fig. 2.1.4. LC-aNAAT sensitivity and specificity for detection of lymph node TB in lymph node aspirate and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; LN: lymph node; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. Should LC-aNAATs on pleural tissue be used to diagnose pleural TB in adults and adolescents with signs and symptoms of pleural TB, against an MRS? From two Xpert Ultra studies (105 participants), LC-aNAAT sensitivities were 80% and 100%, and specificities were 75% and 86% (Fig. 2.1.5); the certainty of evidence was low for sensitivity and very low for specificity. Only data on Xpert Ultra were included in the evaluation to answer this PICO question, as data on Truenat were not available. Given known challenges with culture- based confirmation of TB using this sample, the data using the CRS were also considered. The use of the CRS increased specificity of the LC-aNAAT on pleural tissue to 94\u201397%, but it decreased sensitivity to 54\u201381%6 (see Web Annex B.3). Fig. 2.1.5. LC-aNAAT sensitivity and specificity for detection of pleural TB in pleural tissue and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. 6 Data were not pooled due to the limited number of studies. Study Hoel 2020 Hoel 2020a Spencer-Gomes 2021 Yu 2022 Sharma 2023 Minnies 2021 Antel 2020 Christopher 2021 Slail 2023 TP 3 4 7 3 16 18 7 15 1 FP 0 0 4 8 34 16 14 12 2 FN 0 0 0 0 2 3 2 7 1 TN 2 11 7 11 48 47 50 89 1 Sensitivity (95% CI) 1.00 [0.29, 1.00] 1.00 [0.40, 1.00] 1.00 [0.59, 1.00] 1.00 [0.29, 1.00] 0.89 [0.65, 0.99] 0.86 [0.64, 0.97] 0.78 [0.40, 0.97] 0.68 [0.45, 0.86] 0.50 [0.01, 0.99] Specificity (95% CI) 1.00 [0.16, 1.00] 1.00 [0.72, 1.00] 0.64 [0.31, 0.89] 0.58 [0.33, 0.80] 0.59 [0.47, 0.69] 0.75 [0.62, 0.85] 0.78 [0.66, 0.87] 0.88 [0.80, 0.94] 0.33 [0.01, 0.91] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Sharma 2023 TP 18 FP 36 FN 0 TN", "46 Sensitivity (95% CI) 1.00 [0.81, 1.00] Specificity (95% CI) 0.56 [0.45, 0.67] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Gao 2021 Christopher 2021 TP 9 12 FP 13 4 FN 0 3 TN 39 25 Sensitivity (95% CI) 1.00 [0.66, 1.00] 0.80 [0.52, 0.96] Specificity (95% CI) 0.75 [0.61, 0.86] 0.86 [0.68, 0.96] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "2. Recommendations for diagnosis of TB disease 17 Should LC-aNAATs on pleural fluid be used to diagnose pleural TB in adults and adolescents with signs and symptoms of pleural TB, against an MRS? LC-aNAAT summary sensitivity and specificity were 74.0% (95% CI: 60.8\u201383.9) and 88.1% (95% CI: 78.8\u201393.6), respectively, from 13 Xpert Ultra studies (1041 participants) ( Fig. 2.1.6). The certainty of evidence was low for sensitivity and very low for specificity. Only one study (Jose 2024) provided accuracy estimates for pleural fluid for Truenat MTB Plus (88 participants), with sensitivity of 100% (95% CI: 0.03\u2013100) and specificity of 100% (95% CI: 0.95\u2013100). Similar to lymph node fluid and pleural tissue, the data using the CRS were also considered for this sample type. The use of the CRS increased specificity of LC-aNAATs on pleural fluid to 99.2% (95% CI: 95.2%\u201399.9%) but decreased sensitivity to 71.3% (95% CI: 64.3%\u201377.4%) (see Web Annex B.3 ). Only data on Xpert Ultra were included in the evaluation to answer this PICO question. Data on Truenat were limited. Fig. 2.1.6. LC-aNAAT sensitivity and specificity for detection of pleural TB in pleural fluid and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. Should LC-aNAATs on synovial fluid be used to diagnose bone or joint TB in adults and adolescents with signs and symptoms of bone or joint TB, against an MRS? LC-aNAAT summary sensitivity and specificity were 96.6% (95% CI: 87.2\u201399.1) and 91.1% (95% CI: 80.8\u201396.2), respectively, from three Xpert Ultra studies (126 participants) (Fig. 2.1.7); the certainty of evidence was low. Similar to other extrapulmonary TB sample types, the data using the CRS were also considered. The use of the CRS increased specificity of the LC-aNAAT on synovial fluid to 97.0% (95% CI: 85.0\u2013100.0), whereas the impact on sensitivity was minimal (96%) and largely involved tightening of the confidence interval (95% CI: 91\u201399%). Only data on Xpert Ultra were included in the evaluation to answer this PICO question. Data on Truenat were limited. Study Minnies 2023 Penata 2021 Spencer-Gomes 2021 Slail 2023 Wang 2020 Wang 2019 Wu 2019 Mekkaoui 2021 Christopher 2021 Gao 2021 Perez-Risco 2018 Makambwa 2019 Hoel 2020 TP 12 3 3 26 46 48 17 6 4 3 10 13 0 FP 9 6", "2 21 1 18 30 1 9 10 0 6 0 FN 0 0 0 5 9 11 6 3 2 3 11 22 1 TN 59 84 6 127 83 33 72 67 65 45 3 8 12 Sensitivity (95% CI) 1.00 [0.74, 1.00] 1.00 [0.29, 1.00] 1.00 [0.29, 1.00] 0.84 [0.66, 0.95] 0.84 [0.71, 0.92] 0.81 [0.69, 0.90] 0.74 [0.52, 0.90] 0.67 [0.30, 0.93] 0.67 [0.22, 0.96] 0.50 [0.12, 0.88] 0.48 [0.26, 0.70] 0.37 [0.21, 0.55] 0.00 [0.00, 0.97] Specificity (95% CI) 0.87 [0.76, 0.94] 0.93 [0.86, 0.98] 0.75 [0.35, 0.97] 0.86 [0.79, 0.91] 0.99 [0.94, 1.00] 0.65 [0.50, 0.78] 0.71 [0.61, 0.79] 0.99 [0.92, 1.00] 0.88 [0.78, 0.94] 0.82 [0.69, 0.91] 1.00 [0.29, 1.00] 0.57 [0.29, 0.82] 1.00 [0.74, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Jose 2024 TP 1 FP 0 FN 0 TN 77 Sensitivity (95% CI) 1.00 [0.03, 1.00] Specificity (95% CI) 1.00 [0.95, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 18 Fig. 2.1.7. LC-aNAAT sensitivity and specificity for detection of bone or joint TB in synovial fluid or tissue and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. Should LC-aNAATs on peritoneal fluid be used to diagnose peritoneal TB in adults and adolescents with signs and symptoms of peritoneal TB, against an MRS? The sensitivities of the LC-aNAATs ranged from 33% to 67%, and the specificities from 94% to 100%, from three Xpert Ultra studies (69 participants); the certainty of evidence was very low for sensitivity and low for specificity (Fig. 2.1.8). Only data on Xpert Ultra were included in the evaluation to answer this PICO question. Data on Truenat were limited. Fig. 2.1.8. LC-aNAAT sensitivity and specificity for detection of peritoneal TB in peritoneal fluid and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. Study Jose 2024 TP 0 FP 0 FN 0 TN 7 Sensitivity (95% CI) Not estimable Specificity (95% CI) 1.00 [0.59, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Jose 2024 TP 3 FP 0 FN 0 TN 29 Sensitivity (95% CI) 1.00 [0.29, 1.00] Specificity (95% CI) 1.00 [0.88, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Penata 2021 Mekkaoui 2021 Slail 2023 Sun 2019 Perez-Risco 2018 TP 0 3 3 50 7 FP 0 3 2 1 0 FN 0 0 0 2 1 TN 6 21 8 33 0 Sensitivity (95% CI) Not estimable 1.00 [0.29, 1.00] 1.00 [0.29, 1.00] 0.96 [0.87, 1.00] 0.88 [0.47, 1.00] Specificity (95% CI) 1.00 [0.54, 1.00] 0.88 [0.68, 0.97] 0.80 [0.44, 0.97] 0.97 [0.85, 1.00] Not estimable Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Jose 2024 TP 0 FP 1 FN 1 TN 14 Sensitivity (95% CI) 0.00 [0.00, 0.97] Specificity (95% CI) 0.93 [0.68, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95%", "CI) 0 0.2 0.4 0.6 0.8 1 Study Penata 2021 Slail 2023 Perez-Risco 2018 TP 2 1 1 FP 0 1 0 FN 1 1 2 TN 43 17 0 Sensitivity (95% CI) 0.67 [0.09, 0.99] 0.50 [0.01, 0.99] 0.33 [0.01, 0.91] Specificity (95% CI) 1.00 [0.92, 1.00] 0.94 [0.73, 1.00] Not estimable Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "2. Recommendations for diagnosis of TB disease 19 Should LC-aNAATs on pericardial fluid be used to diagnose pericardial TB in adults and adolescents with signs and symptoms of pericardial TB, against an MRS? LC-aNAAT summary sensitivity and specificity were 84.0% (95% CI: 73.9\u201390.7) and 86.6% (95% CI: 79.5\u201391.5), respectively, from three Xpert Ultra studies (202 participants); certainty of evidence was low for both sensitivity and specificity (Fig. 2.1.9). Fig. 2.1.9. LC-aNAAT sensitivity and specificity for detection of pericardial TB in pericardial fluid and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by decreasing sensitivity. Should LC-aNAAT on extrapulmonary specimens be used to diagnose rifampicin resistance in adults and adolescents with presumed extrapulmonary TB? LC-aNAAT summary sensitivity and specificity were 100.0% (95% CI: 93.4\u2013100.0) and 99.4% (95% CI: 92.1\u2013100.0), respectively, from 13 Xpert Ultra studies (446 participants) (Fig. 2.1.10); certainty of evidence was high for both sensitivity and specificity. Fig. 2.1.10. LC-aNAAT sensitivity and specificity for detection of pericardial TB in pericardial fluid and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by sensitivity. Study Mekkaoui 2021 Penata 2021 Minnies 2023 Alomatu 2023 Slail 2023 TP 0 0 49 12 2 FP 0 0 14 2 1 FN 0 0 8 3 1 TN 19 15 69 27 14 Sensitivity (95% CI) Not estimable Not estimable 0.86 [0.74, 0.94] 0.80 [0.52, 0.96] 0.67 [0.09, 0.99] Specificity (95% CI) 1.00 [0.82, 1.00] 1.00 [0.78, 1.00] 0.83 [0.73, 0.90] 0.93 [0.77, 0.99] 0.93 [0.68, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Hoel 2020a Huang 2021 Huerga 2023 Mekkaoui 2021 Minnies 2021 Penata 2021 Sharma 2020 Sharma 2021 Sharma 2023 Spencer-Gomes 2021 Sun 2019 Wang 2019 Wang 2020 Wu 2019 Chin 2019 Slail 2023 TP 2 1 1 0 1 1 8 11 2 0 9 6 5 4 0 3 FP 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 FN 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 TN 4 5 6 36 8", "26 37 24 14 11 38 23 21 23 3 160 Sensitivity (95% CI) 1.00 [0.16, 1.00] 1.00 [0.03, 1.00] 1.00 [0.03, 1.00] Not estimable 1.00 [0.03, 1.00] 1.00 [0.03, 1.00] 1.00 [0.63, 1.00] 1.00 [0.72, 1.00] 1.00 [0.16, 1.00] Not estimable 1.00 [0.66, 1.00] 1.00 [0.54, 1.00] 1.00 [0.48, 1.00] 1.00 [0.40, 1.00] Not estimable 1.00 [0.29, 1.00] Specificity (95% CI) 1.00 [0.40, 1.00] 1.00 [0.48, 1.00] 1.00 [0.54, 1.00] 1.00 [0.90, 1.00] 1.00 [0.63, 1.00] 1.00 [0.87, 1.00] 1.00 [0.91, 1.00] 1.00 [0.86, 1.00] 1.00 [0.77, 1.00] 1.00 [0.72, 1.00] 1.00 [0.91, 1.00] 1.00 [0.85, 1.00] 1.00 [0.84, 1.00] 1.00 [0.85, 1.00] 1.00 [0.29, 1.00] 0.98 [0.95, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 20 Cost\u2013effectiveness analysis This section deals with the following additional question: What are the comparative costs, affordability and cost\u2013effectiveness of implementation of LC-aNAATs? WHO commissioned a systematic review to identify, evaluate and summarise the evidence on cost, affordability and cost-effectiveness of LC-aNAATs, among other technologies. A total of 1534 studies were identified in the original search; after removing duplicates, 736 potentially relevant studies were screened. Of these, 107 were assigned for full-text review and were evaluated against the inclusion and exclusion criteria, and 29 studies were included in the final systematic review. Of the 29 included studies, 22 (76%) assessed Xpert MTB/RIF, six (21%) assessed Xpert Ultra, and one study (3%) evaluated Truenat tests (both Truenat MTB Plus and Truenat MTB-RIF Dx). Ten of the studies evaluating Xpert MTB/RIF were cost\u2013 effectiveness analyses, and 12 were cost analyses. All the included Xpert Ultra studies and the study evaluating Truenat were cost\u2013effectiveness analyses. The cost-effectiveness analysis on Xpert was considered because of similarity between two technologies and scarcity of the data on Ultra. The studies included in the review were diverse, were conducted across various settings and covered all income levels. This broad spectrum of research provided a comprehensive view of the economic evidence on LC-aNAATs, with a focus on adults. Only three cost\u2013effectiveness analyses included children. There were various comparator tests, including smear and culture. Most of the studies included sputum specimens. Six of the 10 cost\u2013effectiveness analyses on Xpert MTB/RIF presented results in natural units (additional people with TB detected), and the other four presented utility outcomes (quality-adjusted life years and disability-adjusted life years [DALYs]). The findings from the cost\u2013effectiveness analyses showed that Xpert MTB/RIF was generally cost effective across the included studies when compared with smear or culture, except for one study from Thailand, where TB LAMP was the dominant strategy. In contrast, there was more heterogeneity in the methodology used in the cost\u2013effectiveness studies for Xpert Ultra, and the findings showed that, for the Xpert Ultra versus sputum smear microscopy (SSM), an incremental cost\u2013effectiveness ratio (ICER) ranged from US$ 72.72 to US$ 160.23 per DALY averted. In the only study on Truenat, it was found to be cost effective for children in India compared with Xpert MTB/RIF, with an ICER of US$ 94.72 per DALY averted. In general LC-aNAATs are likely to be cost effective across various settings when compared", "2. Recommendations for diagnosis of TB disease 21 User perspective This section deals with the following question: Are there implications for user preferences and values, patient equity, accessibility, feasibility and human rights from the implementation of Xpert MTB/ RIF and Xpert Ultra? This review included 49 qualitative studies, of which 17 were identified in the updated search (since 2022). All studies about LC-aNAATs for detection of TB and DR-TB were conducted in high TB burden settings in Africa, Asia and Eastern Europe. Two studies provided user perspectives on Xpert Ultra and the rest on Xpert MTB/RIF or other rapid molecular tests. The studies about Xpert Ultra were conducted in Africa and Eastern Europe and focused on all people with presumptive TB, DR-TB and extrapulmonary TB. Although standard Xpert MTB/RIF has been superseded by Xpert Ultra and other rapid NAATs, qualitative evidence for the latter NAATs is limited. Whereas LC-NAATs are generally valued for their accuracy, ease of use and potential to reduce time to diagnosis, the most recent generation of NAATs, such as Xpert Ultra, are valued for their greater accuracy in hard-to-diagnose patients, ease of implementation on existing GeneXpert platforms and ease of integration with rapid testing for other diseases. Challenges limiting the realization of these values for more recent NAATs are similar to those with Xpert MTB/RIF \u2013 that is, weak infrastructure, fragmented systems, heavy workloads, and limited availability of NAATs and their supplies. We recommend that qualitative studies be conducted to ascertain perspectives on concurrent use of NAATs. There was high confidence in the evidence contributing to the findings of this review. More details on the qualitative evaluation of LC-aNAATs are available in Web Annex B.10. User preferences and values Findings from Xpert MTB/RIF studies showed that providers valued its utility in making a diagnosis of drug resistance in people living with HIV, accuracy and resulting confidence in the test, rapid turnaround times, low costs of diagnostic testing for patients, and improved patient\u2013 provider relationships. Providers also valued the diversity of sample types that can be analysed by the test. Laboratory personnel valued its ease of use, and they reported increased staff satisfaction compared with sputum microscopy. People with TB valued receiving an accurate diagnosis, avoiding diagnostic delays and having low costs associated with diagnostic testing. Compared with Xpert MTB/RIF, providers valued Xpert Ultra\u2019s capacity for improving TB case detection among hard-to-diagnose patients (those with extrapulmonary TB,", "paediatric TB or coinfection with HIV) and detecting more people with TB. Compared with Xpert MTB/RIF, providers valued Xpert Ultra for its ease of implementation and integration with testing for other diseases (made possible by its having been built on existing Xpert platforms). Acceptability of Xpert Ultra among providers seemed high, but there was uncertainty about its accuracy, potentially leading to reduced trust and litigation in the event of a false diagnosis.", "WHO consolidated guidelines on tuberculosis: Fourth edition 22 Patient equity The limited availability of Xpert Ultra in health facilities and the high costs incurred by patients and health facilities for its use were reported as concerns in terms of equity. Acceptability There were challenges to using Xpert MTB/RIF in the health care system. These challenges included underuse of the test and delays in the diagnostic pathway because of poor sample quality, insufficient resources and maintenance of the testing platforms, lack of functional data connectivity systems or record systems, inefficient patient flows, unavailability of updated clinical guidelines, and poor ownership of and accountability for the tests by health facilities. Overreliance on test results, rather than clinical judgement, and a lack of data-driven implementation processes were reported. Access to the test may be limited owing to lack of sustainable funding, restrictions by donors, poor referral systems, dependence on outreach workers, unavailability of community TB diagnostic facilities and too many eligibility restrictions. Feasibility As with Xpert MTB/RIF, implementation of Xpert Ultra could be hindered by infrastructural problems, such as power outages, staff shortages, limited availability of transportation for sputum samples and limited availability of Xpert testing platforms in health facilities. Implementation considerations \u2022 Diagnostic products in the low-complexity classes of tests should be prequalified by WHO or approved by another regulator before clinical use. \u2022 Diagnostic test manufacturers, laboratory and programme managers, and policy-makers should be educated on the WHO PQ process for TB IVDs (https://extranet.who.int/prequal/). \u2022 Ensuring sufficient volume and specimen quality is important to obtain accurate results. \u2022 Safe waste disposal of used test consumables needs to be planned in advance to minimize environmental risk. \u2022 Trace positive results on respiratory samples may present false-positive results for TB disease (M. tb. non-viable but DNA detected) in those that are HIV negative or not at risk for HIV, and those with a prior history of TB and an end of treatment within the last 5 years. \u2022 For tests that do not have integrated rifampicin-resistance detection as an all-in-one test, reflex testing for resistance should be performed at the same time for all TB-positive patients to support universal access to DST for rifampicin, at a minimum, and to reduce the risk of loss to follow-up. \u2022 In settings with a very low prevalence of rifampicin resistance7, i.e. less than 2%, a positive test result for rifampicin resistance may represent a false positive", "result, and indicate a need for further testing with an alternative method or, at a minimum, repeat testing. 7 The 2% prevalence was used as the lowest one in evidence synthesis and analysis to inform GDG meeting. At this prevalence level the number of false-positive results amounted to 19 out of 1000 eligible patients tested and equalized number of true- positive results.", "2. Recommendations for diagnosis of TB disease 23 \u2022 If rifampicin resistance is detected, further resistance testing for fluoroquinolones and bedaquiline is essential to guide selection of a shorter multidrug-resistant TB or rifampicin- resistant TB (MDR/RR-TB) treatment regimen. \u2022 Use of a higher volume of CSF (\u22656 mL) with concentration, where possible, is encouraged to increase the sensitivity of LC-aNAATs. Monitoring and evaluation \u2022 Track unsuccessful and indeterminate test result rates for currently recommended products and new products to be introduced in this class. \u2022 Monitor the proportion of trace results from paucibacillary samples (e.g. CSF), including those that are culture-positive or culture-negative. \u2022 Undertake surveillance to monitor the frequency of mutations (e.g. I491F mutation) outside of a rpoB rifampicin-resistance determining region (RRDR) over time. \u2022 Monitor the proportion of people with bacteriologically confirmed TB without a rifampicin- resistance result or further recommended drug susceptibility reflex testing over time. Research priorities \u2022 Review the field performance of the current technologies used in routine practice (programmatic settings). \u2022 Conduct operational research to ensure that tests are used optimally in terms of both clinical efficiency and cost efficiency in intended settings. \u2022 Evaluate the impact of LC-aNAAT testing on patient-important outcomes (cure, mortality, time to diagnosis and time to start of treatment). \u2022 Evaluate the strengths, weaknesses and cost differences of different LC-aNAAT products to inform country selection. \u2022 Evaluate the different classes of tests, including LC-aNAATs, to determine which classes or testing strategies yield superior diagnostic accuracy, cost\u2013effectiveness and impact on equity and acceptability. \u2022 Evaluate the impact on incremental accuracy and case detection and the cost\u2013effectiveness of alternative sample types that are easier to collect. \u2022 Evaluate the individual product performance with different paediatric and extrapulmonary TB sample types. \u2022 Develop new tools that are rapid, affordable, feasible and acceptable to children and their parents. \u2022 Optimize or develop tests or simple pre-step sample handling procedures for extrapulmonary TB. \u2022 Identify an improved reference standard that accurately defines TB disease in children, paucibacillary specimens, and people who cannot produce sputum, because the sensitivity of all available diagnostics is suboptimal. \u2022 Develop and apply standardized methods for cost\u2013effectiveness and economic studies, to limit variability.", "WHO consolidated guidelines on tuberculosis: Fourth edition 24 2.1.2 Moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid Rapid detection of TB and rifampicin resistance is increasingly available as new technologies are developed and adopted by countries. However, what has also emerged is the relatively high burden of isoniazid-resistant, rifampicin-susceptible TB that is often undiagnosed. Globally, isoniazid-resistant, rifampicin-susceptible TB is estimated to occur in 13.1% (95% CI: 9.9\u201316.9%) of new cases and 17.4% (95% CI: 0.5\u201354.0%) of previously treated cases (1). A new class of technologies has come to market with the potential to address this gap. Several manufacturers have developed moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid on high throughput platforms for use in laboratories. The tests belonging to this class are faster and less complex to perform than phenotypic culture- based drug susceptibility testing (DST) and line probe assays (LPA). They have the advantage of being largely automated following the sample preparation step. Moderate complexity automated NAATs may be used as an initial test for detection of TB and resistance to both first-line TB drugs simultaneously (rifampicin and isoniazid). They offer the potential for the rapid provision of accurate results (important to patients) and for testing efficiency where high volumes of tests are required daily (important to programmes). Hence, these technologies are suited to areas with a high population density and rapid sample referral systems. Table 2.1.2.1 Class criteria for MC-aNAATs Purpose Detection of TB and resistance to rifampicin and isoniazid Principle of action Nucleic acid amplification testing Complexity Reagents Reagents are available within standardized kits and may have temperature requirements for storage. The sample is added automatically or manually to a disposable sealed container for testing. Skills Moderate technical skills (i.e., multiple sample or reagent handling steps, precision pipetting may be required, molecular workflows may be required) Pipetting One or more non-precision or precision pipetting steps required by the procedure. Testing Procedure May require multiple specimen treatment steps before transferring the specimen into a sealed test container for automated processing. Automated or manual DNA extraction Automated real-time PCR Results generation Type of test result reporting Automated Setting of use Laboratory (special infrastructure may be required)", "2. Recommendations for diagnosis of TB disease 25 Recommendation 5. In people with signs and symptoms of pulmonary TB, moderate complexity automated NAATs may be used on respiratory samples for the detection of pulmonary TB, and of rifampicin and isoniazid rsesistance, rather than culture and phenotypic DST. (Conditional recommendation, moderate certainty of evidence for diagnostic accuracy) There are several subgroups to be considered for this recommendation: \u2022 The recommendation is based on evidence of diagnostic accuracy in respiratory samples of adults with signs and symptoms of pulmonary TB. \u2022 The recommendation applies to people living with HIV (studies included a varying proportion of such individuals); performance on smear-negative samples was reviewed but was only available for TB detection, not for rifampicin and isoniazid resistance, and data stratified by HIV status were not available. \u2022 The recommendation applies to adolescents and children based on the generalization of data from adults; an increased rate of indeterminate results may be found with paucibacillary TB disease in children. \u2022 The review did not consider extrapolation of the finding for use in people with extrapulmonary TB and testing on non-sputum samples because data on diagnostic accuracy of technologies in the class for non-sputum samples were limited. Justification and evidence The WHO Global TB Programme initiated an update of the current guidelines and commissioned a systematic review on the use of moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid in people with signs and symptoms of TB. Three PICO questions were designed to form the basis for the evidence search, retrieval and analysis: 1. Should moderate complexity automated NAATs be used on respiratory samples in people with signs and symptoms of pulmonary TB for detection of pulmonary TB, as compared with culture? 2. Should moderate complexity automated NAATs be used on respiratory samples in people with signs and symptoms of pulmonary TB for detection of resistance to rifampicin, as compared with culture-based phenotypic DST? 3. Should moderate complexity automated NAATs be used on respiratory samples in people with signs and symptoms of pulmonary TB for detection of resistance to isoniazid, as compared with culture-based phenotypic DST? A comprehensive search of the following databases (PubMed, Embase, BIOSIS, Web of Science, LILACS and Cochrane) for relevant citations was performed. The search was restricted to the period January 2009 to July 2020. Reference lists from included studies were also searched. No language restriction", "WHO consolidated guidelines on tuberculosis: Fourth edition 26 the diagnostic companies were contacted for reports of their internal validation data. Studies were also included from the WHO public call for submission of data. Mycobacterial culture was used as the reference standard for evaluation of Mtb detection. Resistance detection was compared with a phenotypic DST reference standard and a composite reference standard (that combines phenotypic and genotypic DST results) in studies where both had been performed. Bivariate random-effects meta-analyses were performed using Stata software, to obtain pooled sensitivity and specificity estimates with 95% CIs for rifampicin resistance, isoniazid resistance and Mtb detection. Where only a limited number of studies were available, descriptive analyses were conducted. For meta-analysis, studies were first meta-analysed separately for each test. Studies from all the tests were then used to obtain a pooled estimate for all technologies. To decide whether pooling of all the tests would give meaningful estimates, various criteria for pooling were developed and agreed upon by the GDG panel before they were applied. Data were also evaluated and visualized using head-to-head comparisons of the tests with Xpert\u00ae MTB/RIF or any other WHO-recommended test. Data for all the index platforms were only pooled to answer PICO questions if they met the preconditions given in Table 2.1.2.2 and fulfilled either Condition 1 or Condition 2. Table 2.1.2.2 Criteria for pooling studies on moderate complexity automated NAATs Parameters Sensitivity Specificity Preconditions n \u226550 culture-positive TB n \u2265100 culture-negative TB Condition 1 (pool based on clinical grounds) The pooled estimate of one test lies within \u00b15% of the overall pooled estimate The pooled estimate of one test lies within \u00b12% of the overall pooled estimate Condition 2 (pool based on statistical grounds) The pooled estimate for one test lies within 95% CI of the overall pooled estimate AND The pooled estimate for one test lies within \u00b110% of the overall pooled estimate The pooled estimate for one test lies within 95% CI of the overall pooled estimate AND The pooled estimate for one test lies within \u00b15% of the overall pooled estimate CI: confidence interval; n: number; NAAT: nucleic acid amplification test; TB: tuberculosis. Data synthesis was structured around the three preset PICO questions, as outlined below. Three web annexes8 give additional information, as follows: \u2022 details of studies included in the current analysis ( Web Annex 1.3: Moderate complexity automated NAATs; \u2022 a summary of the results", "2. Recommendations for diagnosis of TB disease 27 \u2022 a summary of the GDG panel judgements ( Web Annex 3.3: Moderate complexity automated NAATs). PICO 1: Should moderate complexity automated NAATs be used on respiratory samples in people with signs and symptoms of pulmonary TB for detection of pulmonary TB, as compared with culture? A total of 29 studies with 13 852 specimens provided data for evaluating TB detection from the five index tests (Fig. 2.1.2.1). Of these 29 studies, 12 were conducted on the Abbott RealTime MTB test, six on FluoroType MTB, four on FluoroType MTBDR, five on BD MAX and two on the cobas MTB test. The reference standard for each of these studies for TB detection was mycobacterial culture. Of the 29 studies, 16 (55%) had high or unclear risk of bias because they tested specimens before inclusion in the study, used convenience sampling or did not report the method of participant selection. Thus, the evidence was downgraded one level for risk of bias. Overall, the certainty of the evidence was moderate for sensitivity and high for specificity. Fig. 2.1.2.1 Forest plot of included studies for TB detection with culture as the reference standard CI: confidence interval; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive. The overall sensitivity in these 29 studies ranged from 79% to 100%, and the specificity from 60% to 100%. The pooled sensitivity was 93.0% (95% CI: 90.9\u201394.7%) and the pooled specificity was 97.7% (95% CI: 95.6\u201398.8%).", "WHO consolidated guidelines on tuberculosis: Fourth edition 28 PICO 2: Should moderate complexity automated NAATs be used on respiratory samples in people with signs and symptoms of pulmonary TB for detection of resistance to rifampicin, as compared with culture-based phenotypic DST? A total of 18 studies with 2874 specimens provided data for resistance testing of rifampicin using moderate complexity automated NAATs ( Fig. 2.1.2.2). Of these 18 studies, nine were conducted on the Abbott RealTi me RIF/INH test, three on FluoroType MTBDR, four on BD MAX and two on the cobas RIF/INH test. The reference standard for each of these studies for resistance detection was phenotypic DST, using a composite reference standard with both phenotypic DST and sequencing results. Eight (44%) of the 18 studies had high or unclear risk of bias because they did not report participant selection or tested specimens before inclusion in the study. Fig. 2.1.2.2 Forest plot of included studies for rifampicin resistance detection with phenotypic DST as the reference standard CI: confidence interval; DST: drug susceptibility testing; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive. The overall sensitivity for rifampicin resistance in these 18 studies ranged from 88% to 100% and the specificity from 98% to 100%. The pooled sensitivity was 96.7% (95% CI: 93.1\u2013 98.4%) and the pooled specificity was 98.9% (95% CI: 97.5\u201399.5%). In determining rifampicin resistance, the results from genetic sequencing (genotypic DST) were obtained where possible, and a composite reference standard was developed that combined the results from phenotypic and genotypic DST. For rifampicin resistance detection, the diagnostic test accuracy of moderate complexity automated NAATs was similar for phenotypic DST and the composite reference standard.", "2. Recommendations for diagnosis of TB disease 29 PICO 3: Should moderate complexity automated NAATs be used on respiratory samples in people with signs and symptoms of pulmonary TB for detection of resistance to isoniazid, as compared with culture-based phenotypic DST? A total of 18 studies with 1758 specimens provided data for resistance testing of isoniazid using moderate complexity automated NAATs ( Fig. 2.1.2.3). Of these 18 studies, nine were conducted on the Abbott RealTi me RIF/INH test, three on FluoroType MTBDR, four on BD MAX and two on the cobas MTB-RIF/INH test. The reference standard for each of these studies for resistance detection was phenotypic DST, and a composite reference standard with both phenotypic DST and sequencing results. Eight (44%) of the 18 studies had high or unclear risk of bias, because participant selection was not reported or prior testing was done on the included specimens. Fig. 2.1.2.3 Forest plot of included studies for isoniazid resistance detection with phenotypic DST as the reference standard CI: confidence interval; DST: drug susceptibility testing; FN: false negative; FP: false positive; RIF: rifampicin; TB: tuberculosis; TN: true negative; TP: true positive. The overall sensitivity for isoniazid resistance in these 18 studies ranged from 58% to 100% and the specificity from 94% to 100%. The pooled sensitivity was 86.4% (95% CI: 82.1\u2013 89.8%) and the pooled specificity was 99.8% (95% CI: 98.3\u201399.8%). In determining isoniazid resistance, the results from genetic sequencing (genotypic DST) were obtained where possible, and a composite reference standard was developed that combined the results from phenotypic and genotypic DST. For detecting isoniazid resistance, the diagnostic test accuracy of phenotypic DST was similar to that of the composite reference standard. Cost\u2013effectiveness analysis This section answers the following additional question: What is the comparative cost, affordability and cost\u2013effectiveness of implementation of moderate complexity automated NAATs?", "WHO consolidated guidelines on tuberculosis: Fourth edition 30 A systematic review was conducted, focusing on economic evaluations of moderate complexity automated NAATs. Four online databases (Embase, Medline, Web of Science and Scopus) were searched for new studies published from 1 January 2010 through 17 September 2020. The citations of all eligible articles, guidelines and reviews were reviewed for additional studies. Experts and test manufacturers were also contacted to identify any additional unpublished studies. The objective of the review was to summarize current economic evidence and further understand the costs, cost\u2013effectiveness and affordability of moderate complexity automated NAATs. Several commercially available tests were included as eligible tests in the moderate complexity automated NAATs category; however, no published studies were identified assessing the costs or cost\u2013effectiveness of any of those tests. One unpublished study comparing available data on two technologies from moderate complexity automated NAATs class was identified, and the data from that study are described below. Unpublished data from FIND was provided through direct communication. This costing-only study used time and motion studies combined with a bottom-up, ingredients-based approach to estimate the unit test cost for the two selected technologies. 9 Time and motion studies were conducted at a reference-level laboratory in South Africa. Several important simplifying assumptions were made that may limit the generalizability of the results; for example, 50% of laboratory operations dedicated to TB, a minimum daily throughput of 24 samples or the equivalent of one BD MAX run (24 tests/run), equipment costs fixed at US$ 100 000 for both platforms, a 5% annual maintenance cost, and the standard 3% discount rate and 10 years expected useful life years. Additional literature searches conducted to look for economic data using similar platforms from non-TB disease areas identified three additional studies from HIV and hepatitis C virus (HCV) with limited cost data: one ( 5) using Abbott RealTime HIV and two on HCV (6,7). Data were limited to cost per unit test kit and are not transferrable to test kit costs for the tests being considered in this review. How large are the resource requirements (costs)? Available unit test costs for two moderate complexity automated NAATs ranged from US$ 18.52 (US$ 13.79\u201340.70) and US$ 15.37 (US$ 9.61\u201337.40), with one study reporting cheaper per-test kit costs and higher operational costs associated with laboratory processing time. Equipment costs were strong drivers of cost variation and will vary across laboratory networks and operations.", "If equipment can be optimally placed or multiplexed to ensure high testing volume, the per-test cost can be minimized. In one-way sensitivity analyses, annual testing volumes varied from fewer than 5000 tests/year to more than 25 000 tests/year. Per-test cost was highly sensitive to testing volume when fewer than 5000 tests were conducted per year; however, unit test costs begin to stabilize between 5000 and 10 000 tests/year, and above 10 000 tests/year, unit cost estimate was robust. When equipment can be multiplexed and used at capacity, per-test cost can be minimized. 9 Data courtesy of H Sohn and W Stevens at FIND (unpublished).", "2. Recommendations for diagnosis of TB disease 31 What is the certainty of the evidence of resource requirements (costs)? Available per-test cost data were unpublished but did include overheads, equipment, building, staff and consumable costs; however, complete quality assessment of the study was not possible. Test cost will vary according to testing volume and laboratory operations. There is limited evidence to assess the important variability across sites, countries and implementation approaches. Does the cost\u2013effectiveness of the intervention favour the intervention or the comparison? No studies were identified that assessed cost\u2013effectiveness for any of the moderate complexity automated NAATs, and extrapolation was not appropriate given differences in standard of care, care cascades and associated costs, operational conditions, testing volume and diagnostic accuracy. Implementation considerations (e.g. test placement, laboratory network and ability of the programme to initiate treatment quickly) are all likely to affect unit test cost and cost\u2013 effectiveness. Economic modelling is needed across various settings to understand the range of cost\u2013effectiveness profiles of moderate complexity automated NAATs, and how they are likely to vary under different operational criteria. Additional details on economic evidence synthesis and analysis are provided in Web Annex B.12: Systematic literature review of economic evidence for NAATs to detect TB and DR-TB in adults and children. User perspective This section answers the following questions about key informants\u2019 views and perspectives on the use of moderate complexity automated NAATs: \u2022 Is there important uncertainty about or variability in how much end-users value the main outcomes? \u2022 What would be the impact on health equity? \u2022 Is the intervention acceptable to key stakeholders? \u2022 Is the intervention feasible to implement? User perspectives on the value, feasibility, usability and acceptability of diagnostic technologies are important in the implementation of such technologies. If the perspectives of laboratory personnel, clinicians, patients and TB programme personnel are not considered, the technologies risk being inaccessible to and underused by those for whom they are intended. To address questions related to user perspective, two activities were undertaken: \u2022 A systematic review of evidence on user perspectives and experiences with NAATs for detection of TB and TB drug resistance (moderate and low complexity automated assays, and high complexity hybridization-based assays) was undertaken from July to November 2020. \u2022 A total of 14 semi-structured interviews with clinicians, programme officers, laboratory staff and patient advocates were conducted in India, Moldova and South Africa from October to November 2020.", "WHO consolidated guidelines on tuberculosis: Fourth edition 32 Systematic review A total of 27 studies were identified that met inclusion criteria, of which 21 were sampled for inclusion in the analysis. All of the sampled studies were published between 2012 and 2020. Of the 21 included studies, 18 were located in high TB burden countries: six in India, four in South Africa, two each in Kenya and Uganda, and one each in Brazil, Cambodia, Myanmar and Viet Nam. One study covered projects in nine countries (Bangladesh, Cambodia, Democratic Republic of the Congo, Kenya, Malawi, Moldova, Mozambique, Nepal and Pakistan). In addition, there was one study located in Eswatini, one in Mongolia and one in Nepal. All studies focused on Xpert MTB/RIF, except for one that focused on Xpert MTB/RIF Ultra (Xpert Ultra). A summary of the core characteristics of studies included in this review is presented in a study characteristics table in Web Annex B.13: User perspectives on NAATs to detect TB and DR-TB: results from qualitative evidence synthesis: systematic review. Interviews The aim of the interviews was to understand participants\u2019 experiences of using the various technologies (i.e. NAATs for detection of TB and TB drug resistance) and their general TB diagnostic experiences. The three countries \u2013 India, Moldova and South Africa \u2013 were selected based on them being on WHO\u2019s list of 30 high MDR-TB burden countries (1) and that index tests have been used to some extent in research contexts within these countries. Due to the short time frame, participants were purposively sampled and approached based on convenience through personal contacts and colleagues. An overview of the participants is given in Table 2.1.2.3 To mask the identity of study participants they were coded by their country (Moldova [M], India [I] or South Africa [S]), their profession (clinician or medical doctor [M], patient advocate/representative [R], laboratory personnel [L] or programme officers [P]) and a number. Table 2.1.2.3 Overview of participants for the end-users\u2019 interviews Moldova India South Africa Clinician or medical doctor 1 1 1 Patient advocate/representative 1 1 1 Laboratory personnel 2a 5a 2 Programme officers 2a 2 1 a Participants were interviewed as a group. Interviews were conducted using Zoom, Skype or phone. Topics discussed included: \u2022 current approach to diagnosing TB, MDR-TB and extensively drug-resistant TB (XDR-TB), including specific challenges; \u2022 experiences with using molecular TB diagnostics and the index tests specifically, including details on steps", "2. Recommendations for diagnosis of TB disease 33 \u2022 overall usefulness of the index tests; \u2022 the feasibility of implementing the index tests; \u2022 the potential impact of the index tests on health equity; and \u2022 how the potential impact of the index tests relates to current policy context. Several important limitations of this approach were noted. Only a few participants were interviewed per country. Owing to the use of Zoom, Skype or phone for interviews, it was not possible to triangulate interview data with other evidence commonly collected through ethnographic approaches (e.g. multiple interviews and informal conversations at the same facility, observations or site visits). In addition, only some of the participants had personal experience with one or all of the index tests, and those participants who did have experience with the tests had used them in research settings rather than for routine practice. More details on these interviews are given in Web Annex B.14: User perspectives on nucleic acid amplification tests for tuberculosis and tuberculosis drug resistance: Interviews study. Findings of the review and interviews The main findings of the systematic review and interviews are given below. Where information is from the review, a level of confidence in the quality evidence synthesis (QES) is given; where it is from interviews, this is indicated with \u2018Interviews\u2019. Is there important uncertainty about or variability in how much end-users value the main outcomes? \u2022 Patients in high burden TB settings value: \u2013 getting an accurate diagnosis and reaching diagnostic closure (finally knowing \u201cwhat is wrong with me\u201d); \u2013 avoiding diagnostic delays because they exacerbate existing financial hardships and emotional and physical suffering, and make patients feel guilty for infecting others (especially children); \u2013 having accessible facilities; and \u2013 reducing diagnosis-associated costs (e.g. travel, missing work) as important outcomes of the diagnostic. QES: moderate confidence \u2022 Moderate complexity automated NAATs meet several preferences and values of clinicians and laboratory staff, in that they: \u2013 are faster than culture-based phenotypic DST (similar to LPA or cartridge-based tests); \u2013 have the advantage of being automated (unlike LPA); \u2013 provide additional clinically relevant drug-resistance information such as high versus low resistance (unlike the current Xpert MTB/RIF cartridge). Interviews What would be the impact on health equity? \u2022 Various factors \u2013 for example, lengthy diagnostic delays, underuse of diagnostics, lack of TB diagnostic facilities at lower levels and too many eligibility restrictions \u2013 hamper access to", "WHO consolidated guidelines on tuberculosis: Fourth edition 34 \u2022 Staff and managers voiced concerns about: \u2013 sustainability of funding and maintenance; \u2013 complex conflicts of interest between donors and implementers; and \u2013 the strategic and equitable use of resources, which negatively affects creating equitable access to cartridge-based diagnostics. QES: high confidence \u2022 Access to clear and comprehensible information for TB patients on what TB diagnostics are available to them and how to interpret results is a vital component of equity, and lack of such access represents an important barrier for patients. Interviews \u2022 New treatment options need to be matched with new diagnostics. It is important to improve access to treatment based on new diagnostics and to improve access to diagnostics for new treatment options. Interviews \u2022 The speed at which WHO guidelines are changing does not match the speed at which many country programmes are able to implement the guidelines. This translates into differential access to new TB diagnostics and treatment: \u2013 between countries (i.e. between those that can and cannot quickly keep up with the rapidly changing TB diagnostic environment); and \u2013 within countries (i.e. between patients who can and cannot afford the private health system that is better equipped to quickly adopt new diagnostics and policies). Interviews \u2022 The identified challenges with the use of NAATs for detection of TB and DR-TB, and accumulated delays, risk compromising the added value as identified by the users, ultimately leading to underuse. The challenges also hamper access to prompt and accurate testing and treatment, particularly for vulnerable groups. QES: high confidence Is the intervention acceptable to key stakeholders? \u2022 Patients can be reluctant to test for TB or MDR-TB because of: \u2013 stigma related to MDR-TB or having interrupted treatment in the past; \u2013 fears of side-effects; \u2013 failure to recognize symptoms; \u2013 inability to produce sputum; and \u2013 cost, distance and travel concerns related to (repeat) clinic visits. QES: high confidence \u2022 Health workers can be reluctant to test for TB or MDR-TB because of: \u2013 TB-associated stigma and consequences for their patients; \u2013 fear of acquiring TB; \u2013 fear from supervisors when reclassifying patients already on TB treatment who turn out to be misclassified; \u2013 fear of side-effects of drugs in children; and \u2013 community awareness of disease manifestations in children. QES: high confidence", "2. Recommendations for diagnosis of TB disease 35 \u2022 In relation to the acceptability of moderate complexity automated NAATs: \u2013 the automation of this class of technologies, which recognizes the high workload of laboratory staff, improves their acceptability; \u2013 in terms of the physical size of the platform and how it fits into the laboratory space and workflow, a smaller footprint may be more acceptable; and \u2013 the number of samples run on the system is acceptable provided that the platform is placed within a laboratory that receives a sufficient sample load to run the system. Interviews Is the intervention feasible to implement? \u2022 The feasibility of all diagnostic technologies is challenged if there is an accumulation of diagnostic delays or underuse (or both) at every step in the process, mainly because of health system factors such as: \u2013 non-adherence to testing algorithms, testing for TB or MDR-TB late in the process, empirical treatment, false negatives due to technology failure, large sample volumes and staff shortages, poor or delayed sample transport and sample quality, poor or delayed communication of results, delays in scheduling follow-up visits and recalling patients, and inconsistent recording of results; \u2013 lack of sufficient resources and maintenance (i.e. stock-outs; unreliable logistics; lack of funding, electricity, space, air conditioners and sputum containers; dusty environment; and delayed or absent local repair option); \u2013 inefficient or unclear workflows and patient flows (e.g. inefficient organizational processes, poor links between providers, and unclear follow-up mechanisms or information on where patients need to go); and \u2013 lack of data-driven and inclusive national implementation processes. QES: high confidence \u2022 The feasibility of moderate complexity automated NAATs is also challenged by: \u2013 how or whether the platform fits into the physical space of the laboratory (considering bench size and weight of the platform) and sample workflow; \u2013 a poorly functioning sample transport system that affects the quality of samples; and \u2013 the need to ensure that clinicians and laboratory staff have time to communicate effectively regarding diagnostic results if the platform is centralized, while also ensuring that the laboratory location is central enough to receive adequate numbers of samples to make the machine worth running. Interviews \u2022 Implementation of new diagnostics must be accompanied by training for clinicians to help them interpret results from new molecular tests and understand how this information is translated into prompt and proper patient management. In the past, with the", "introduction of Xpert MTB/RIF, this has been a challenge. QES: high confidence and interviews \u2022 Introduction of new diagnostics must be accompanied by guidelines and algorithms that support clinicians and laboratories in communicating with each other, such that they can discuss discordant results and interpret laboratory results in the context of drug availability, patient history and patient progress on a current drug regimen. Interviews", "WHO consolidated guidelines on tuberculosis: Fourth edition 36 Implementation considerations Factors to consider when implementing moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid are as follows: \u2022 local epidemiological data on resistance prevalence should guide local testing algorithms, whereas pretest probability is important for the clinical interpretation of test results; \u2022 the cost of a test varies depending on parameters such as the number of samples in a batch and the staff time required; therefore, a local costing exercise should be performed; \u2022 low, moderate and high complexity tests have successive increase in technical competency needs (qualifications and skills) and staff time, which affects planning and budgeting; \u2022 availability and timeliness of local support services and maintenance should be considered when selecting a provider; \u2022 laboratory accreditation and compliance with a robust quality management system (including appropriate quality control) are essential for sustained service excellence and trust; \u2022 training of both laboratory and clinical staff is needed to ensure effective delivery of services and clinical impact; \u2022 use of connectivity solutions for communication of results is encouraged, to improve efficiency of service delivery and reduce time to treatment initiation; \u2022 moderate complexity automated NAATs may already be used programmatically for other diseases \u2013 for example, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), HIV and antimicrobial resistance (AMR) \u2013 which could potentially facilitate implementation of TB testing on shared platforms; \u2022 implementation of moderate complexity automated NAATs requires laboratories with the required infrastructure, space and efficient sample referral systems; \u2022 although these are automated tests, well-trained skilled staff are needed to set up assays and complete maintenance requirements; and \u2022 implementation of these tests should be context specific; thus, it should take into account access issues, especially in remote areas, where less centralized WHO-recommended technologies may be more appropriate. Research priorities Research priorities for moderate complexity automated NAATs for detection of TB and resistance to rifampicin and isoniazid are as follows: \u2022 diagnostic accuracy in specific patient populations (e.g. children, people living with HIV, and patients with signs and symptoms of extrapulmonary TB) and in non-sputum samples; \u2022 impact of diagnostic technologies on clinical decision-making and outcomes that are important to patients (e.g. cure, mortality, time to diagnosis and time to start treatment) in all patient populations; \u2022 impact of specific mutations on treatment outcomes among people with DR-TB; \u2022 use, integration and optimization of", "2. Recommendations for diagnosis of TB disease 37 \u2022 effect of non-actionable results (indeterminate, non-determinate or invalid) on diagnostic accuracy and outcomes that are important to patients; \u2022 operational research on the advantages and disadvantages of individual technologies within the class of moderate complexity automated NAATs; \u2022 effect of moderate complexity automated NAATs in fostering collaboration and integration between disease programmes; and \u2022 the potential utility of detecting katG resistance to identify MDR-TB clones that may be missed because they do not have an RRDR mutation (e.g. the Eswatini MDR-TB clone, which has both the katG S315T and the non-RRDR rpoB I491F mutation). 2.2. Initial diagnostic tests for diagnosis of TB without drug-resistance detection A new class of low-complexity manual NAATs (LC-mNAATs) has now emerged for alternative molecular solutions that have improved accuracy when compared with smear microscopy and very basic infrastructure, power and equipment requirements (e.g. heat block). LC-mNAATs can be performed at the microscopy level and are currently cheaper than other molecular tests. Collectively, these characteristics are useful for testing in constrained settings. However, like smear microscopy, this class of tests does not incorporate rifampicin-resistance detection and therefore requires reflex testing with a complementary solution for drug-resistance determination. 2.2.1 Low-Complexity manual NAATs for detection of TB Diagnostic class description The features shown in Table 2.2.1.1 define the class of LC-mNAATs. Table 2.2.1.1 Class criteria for LC-mNAATs Purpose Detection of TB Principle of action Nucleic acid amplification testing Complexity Reagents Reagents are enclosed in multiple disposable sealed containers not requiring special storage requirements Skills Basic technical skills (e.g. basic pipetting, precision not critical) Pipetting Multiple pipetting steps (maximum of 10) from processed sample to result generation Testing procedure At least three distinct steps: y Specimen treatment step before transferring the specimen into the disposable sealed container y DNA extraction y PCR amplification y Results visualization Type of test result reporting Automated or manual Setting of use Basic laboratory (no special infrastructure needed) DNA: deoxyribonucleic acid; LC-mNAAT: low-complexity manual nucleic acid amplification test; PCR: polymerase chain reaction; TB: tuberculosis. NEW", "WHO consolidated guidelines on tuberculosis: Fourth edition 38 The only product for which eligible data met the class-based performance criteria for LC-mNAATs is Loopamp MTBC Detection Kit (TB LAMP) (Eiken Chemical, Tokyo, Japan) for pulmonary TB. Regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of this diagnostic test. Extrapolation to other brand-specific tests cannot be made, and any new in-class technologies or new indications for the technology currently included in the class will need to be evaluated by WHO PQ and WHO/GTB, respectively. The publication WHO operational handbook on tuberculosis. Module 3: Diagnosis describes the tests included in this class. Recommendations 6. For adults and adolescents with signs or symptoms or who screen positive for pulmonary TB, low-complexity manual NAATs should be used on respiratory samples as initial diagnostic tests for TB rather than smear microscopy or culture. (Strong recommendation, high certainty of evidence) Remarks \u2022 This recommendation applies to all people living with HIV, with the caveat of low to moderate certainty of evidence. However, wherever available, concurrent testing with an LC-aNAAT and LF-LAM is recommended for people living with HIV. For more details, see Section 2.3.1. \u2022 This recommendation was extrapolated to children for use with respiratory samples (including induced sputum and gastric aspirate) based on the generalization of data from adults and very limited data for children, acknowledging the difficulties of collecting sputum specimens from this population. However, wherever available, concurrent testing with an LC-aNAAT on a respiratory and stool samples is recommended for children. For more details, see Section 2.3.2. \u2022 Data on the use of the test with paediatric stool samples were very limited, and there were no data on the use of nasopharyngeal aspirates. The recommendation was, therefore, not extrapolated to these sample types. \u2022 No recommendation was made on test use for extrapulmonary TB due to insufficient data. \u2022 As LC-mNAATs do not provide rifampicin-resistance results, all positive diagnostic tests for TB require follow-up and referral for DST for, at a minimum, rifampicin. Justification and evidence WHO/GTB initiated an update of the previous guidelines and commissioned a systematic review on the use of LC-mNAATs (TB LAMP) for the diagnosis of TB in people with signs and symptoms of TB, or who screened positive for TB.", "2. Recommendations for diagnosis of TB disease 39 Detection of pulmonary TB Should LC-mNAATs on respiratory samples be used to diagnose pulmonary TB in adults and adolescents with signs and symptoms or who screened positive for pulmonary TB, against an MRS? Twenty-six studies (18 297 participants) assessed diagnostic accuracy using sputum specimens and comparing with an MRS. The sensitivities were between 55% and 100%, and the specificities were between 70% and 100% (Fig. 2.2.1.1). The summary sensitivity was 84.1% (95% CI: 78.3\u201388.6), and the summary specificity was 96.1% (95% CI: 94.2\u201397.4). The certainty of evidence for sensitivity and specificity was high. Fig. 2.2.1.1 Forest plot of LC-mNAAT sensitivity and specificity for detection of pulmonary TB in respiratory samples and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by increasing sensitivity. Study Nakiyingi 2018 Spooner 2022 Nliwasa 2016 Xin 2023 Ou 2014 Reddy 2017 Ou 2016 Gelaw 2017 Pham 2018 Odeume 2021 Danfack 2024b Cheng 2020 Danfack 2018 Promsena 2022 Kim 2018 Gray 2016 Danfack 2023 Kaku 2016 Wang 2019 Ou 2019 Mitarai 2011 Yadav 2021 N'Guessan 2016 Wahid 2020 Bojang 2016 Yadav 2017 TP 46 32 26 141 265 119 322 21 292 99 141 128 171 5 56 331 110 60 91 376 107 10 144 42 97 69 FP 3 12 0 4 16 17 147 1 22 17 48 9 12 0 28 52 19 3 10 181 4 1 18 17 12 3 FN 37 24 14 59 110 45 108 7 91 30 33 29 36 1 11 61 20 10 11 44 12 1 13 0 0 0 TN 147 637 193 24 938 514 942 49 571 2490 736 333 290 2 193 1333 205 136 389 2519 36 23 294 39 119 381 Sensitivity (95% CI) 0.55 [0.44, 0.66] 0.57 [0.43, 0.70] 0.65 [0.48, 0.79] 0.70 [0.64, 0.77] 0.71 [0.66, 0.75] 0.73 [0.65, 0.79] 0.75 [0.71, 0.79] 0.75 [0.55, 0.89] 0.76 [0.72, 0.80] 0.77 [0.68, 0.84] 0.81 [0.74, 0.87] 0.82 [0.75, 0.87] 0.83 [0.77, 0.88] 0.83 [0.36, 1.00] 0.84 [0.73, 0.92] 0.84 [0.80, 0.88] 0.85 [0.77, 0.90] 0.86 [0.75, 0.93] 0.89 [0.82, 0.94] 0.90 [0.86, 0.92] 0.90 [0.83, 0.95] 0.91 [0.59, 1.00] 0.92 [0.86, 0.96] 1.00 [0.92, 1.00] 1.00 [0.96, 1.00] 1.00 [0.95, 1.00] Specificity (95% CI)", "0.98 [0.94, 1.00] 0.98 [0.97, 0.99] 1.00 [0.98, 1.00] 0.86 [0.67, 0.96] 0.98 [0.97, 0.99] 0.97 [0.95, 0.98] 0.87 [0.84, 0.88] 0.98 [0.89, 1.00] 0.96 [0.94, 0.98] 0.99 [0.99, 1.00] 0.94 [0.92, 0.95] 0.97 [0.95, 0.99] 0.96 [0.93, 0.98] 1.00 [0.16, 1.00] 0.87 [0.82, 0.91] 0.96 [0.95, 0.97] 0.92 [0.87, 0.95] 0.98 [0.94, 1.00] 0.97 [0.95, 0.99] 0.93 [0.92, 0.94] 0.90 [0.76, 0.97] 0.96 [0.79, 1.00] 0.94 [0.91, 0.97] 0.70 [0.56, 0.81] 0.91 [0.85, 0.95] 0.99 [0.98, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 40 Detection of TB in people living with HIV Should LC-mNAATs on respiratory samples be used to diagnose pulmonary TB in adult and adolescent living with HIV with signs and symptoms of pulmonary TB, against an MRS? In the eight studies (2991 participants) included in this meta-analysis, the sensitivities ranged between 52% and 100%, and the specificities between 27% and 100% ( Fig. 2.2.1.2 ). The summary sensitivity was 77.1% (95% CI: 60.8\u201387.9), and the summary specificity was 95.9% (95% CI: 84.9\u201399.0). The certainty of evidence was low for sensitivity and moderate for specificity. Fig. 2.2.1.2 Forest plot of LC-mNAAT sensitivity and specificity for detection of pulmonary TB in respiratory samples from people living with HIV and MRSa CI: confidence interval; FN: false negative; FP: false positive; HIV: human immunodeficiency virus; LC-mNAAT: low- complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by increasing sensitivity. Detection of TB in children Should LC-mNAATs on respiratory samples be used to diagnose pulmonary TB in children with signs and symptoms of pulmonary TB, against an MRS? Three studies (62 participants, including eight with pulmonary TB) assessed the accuracy of LC-mNAATs for detecting pulmonary TB using respiratory samples (sputum, BAL and tracheal aspirate) and an MRS ( Fig. 2.2.1.3). The sensitivities were between 60% and 100%, and the specificities were between 95% and 100%. The certainty of evidence was very low for sensitivity and low for specificity. Fig. 2.2.1.3 Forest plot of LC-mNAAT sensitivity and specificity for detection of pulmonary TB in respiratory samples and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by increasing sensitivity. Study Nakiyingi 2018 Spooner 2022 Odeume 2021 Nliwasa 2016 Danfack 2023 Danfack 2024b N'Guessan 2016 Danfack 2018 TP 23 32 9 10 51 148 42 36 FP 2 12 3 0 17 53 8 0 FN 21 24 6 5 13 37 3 0 TN 67 637 697 87 124 810 3 11 Sensitivity (95% CI) 0.52 [0.37, 0.68] 0.57 [0.43, 0.70] 0.60 [0.32, 0.84] 0.67 [0.38, 0.88] 0.80 [0.68, 0.89] 0.80 [0.74, 0.86] 0.93 [0.82, 0.99] 1.00 [0.90, 1.00] Specificity (95% CI) 0.97 [0.90, 1.00] 0.98 [0.97, 0.99] 1.00 [0.99, 1.00] 1.00", "[0.96, 1.00] 0.88 [0.81, 0.93] 0.94 [0.92, 0.95] 0.27 [0.06, 0.61] 1.00 [0.72, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Bojang 2016 Promsena 2022 Yadav 2021 TP 1 2 3 FP 0 0 2 FN 0 0 2 TN 15 4 38 Sensitivity (95% CI) 1.00 [0.03, 1.00] 1.00 [0.16, 1.00] 0.60 [0.15, 0.95] Specificity (95% CI) 1.00 [0.78, 1.00] 1.00 [0.40, 1.00] 0.95 [0.83, 0.99] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "2. Recommendations for diagnosis of TB disease 41 Should LC-mNAATs on gastric aspirate be used to diagnose pulmonary TB in children with signs and symptoms of pulmonary TB, against an MRS? Three studies (176 participants, including 14 with pulmonary TB) assessed the accuracy of LC-mNAATs for detecting pulmonary TB using gastric aspirate against a MRS ( Fig. 2.2.1.4). Sensitivity was not estimable for two studies and was 64% in the third study. The specificities were between 93% and 100%. Fig. 2.2.1.4 Forest plot of LC-mNAAT sensitivity and specificity for detection of pulmonary TB in gastric aspirate and MRSa Study Danfack 2024 Promsena 2022 Yadav 2021 TP 9 0 0 FP 9 0 0 FN 5 0 0 TN 121 22 10 Sensitivity (95% CI) 0.64 [0.35, 0.87] Not estimable Not estimable Specificity (95% CI) 0.93 [0.87, 0.97] 1.00 [0.85, 1.00] 1.00 [0.69, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by increasing sensitivity. Should LC-mNAATs on nasopharyngeal aspirate be used to diagnose pulmonary TB in children with signs and symptoms of pulmonary TB, against an MRS? One study (144 participants including 12 with pulmonary TB) assessed the accuracy of LC-mNAATs for detecting pulmonary TB using nasopharyngeal aspirate against an MRS (Fig. 2.2.1.5). The sensitivity was 58% and specificity was 94%. Due to limited data, a recommendation on using LC-mNAATs with nasopharyngeal aspirate for detection of pulmonary TB was not made. Fig. 2.2.1.5 Forest plot of LC-mNAAT sensitivity and specificity for detection of pulmonary TB in nasopharyngeal aspirate and MRSa Study Danfack 2024 TP 7 FP 8 FN 5 TN 124 Sensitivity (95% CI) 0.58 [0.28, 0.85] Specificity (95% CI) 0.94 [0.88, 0.97] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted by increasing sensitivity. Should LC-mNAATs on stool be used to diagnose pulmonary TB in children with signs and symptoms of pulmonary TB, against an MRS? One study (144 participants, including seven with pulmonary TB) assessed", "the accuracy of LC-mNAATs for detecting pulmonary TB using stool against a MRS (Fig. 2.2.1.6). The sensitivity was 100% and specificity was 92%. The certainty of evidence was very low for sensitivity and moderate for specificity. Due to limited data, a recommendation on using LC-mNAATs with stool for detection of pulmonary TB was not made.", "WHO consolidated guidelines on tuberculosis: Fourth edition 42 Fig. 2.2.1.6 Forest plot of LC-mNAAT sensitivity and specificity for detection of pulmonary TB in stool and MRS CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Detection of TB meningitis Should LC-mNAATs on CSF be used to diagnose TB meningitis in adults and adolescents with signs and symptoms of TB meningitis, against an MRS? Two studies (70 participants, including three with TB meningitis) assessed the accuracy of LC-mNAATs for detecting TB meningitis using CSF and an MRS (Fig. 2.2.1.7). Estimated sensitivity and specificity were both 100% in one study, and 0% and 97%, respectively, in the other. The certainty of evidence was very low for sensitivity and low for specificity. Due to limited data, a recommendation on using LC-mNAATs with CSF for detection of TB meningitis was not made. Fig. 2.2.1.7 Forest plot of LC-mNAAT sensitivity and specificity for detection of TB meningitis in CSF and MRS CI: confidence interval; CSF: cerebrospinal fluid; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Detection of extrapulmonary TB Should LC-mNAATs on lymph node tissue be used to diagnose lymph node TB in adults and adolescents with signs and symptoms of lymph node TB, against an MRS? Three studies (95 participants, including 35 people with TB) assessed the accuracy of LC-mNAATs for detecting lymph node TB using lymph node tissue from biopsy and an MRS ( Fig. 2.2.1.8). The estimated sensitivities were between 93% and 100%, and specificities were between 88% and 100%. The summary sensitivity was 94.3% (95% CI: 79.8\u201398.6), and the summary specificity was 90.0% (95% CI: 79.5\u201395.4). The certainty of evidence was low for both sensitivity and specificity. Due to limited data, a recommendation on using LC-mNAATs with lymph node tissue for the detection of lymph node TB was not made. Study Danfack 2024 TP 7 FP 11 FN 0 TN 126 Sensitivity (95% CI) 1.00 [0.59, 1.00] Specificity (95% CI) 0.92 [0.86, 0.96] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Danfack 2024a Singh 2021 TP 0 1 FP 2 0 FN 2 0 TN 61 4 Sensitivity (95% CI) 0.00 [0.00, 0.84] 1.00", "2. Recommendations for diagnosis of TB disease 43 Fig. 2.2.1.8 Forest plot of LC-mNAAT sensitivity and specificity for detection of lymph node TB in lymph node tissue and MRS CI: confidence interval; FN; false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; LN: lymph node; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Should LC-mNAATs on pleural fluid be used to diagnose pleural TB in adults and adolescents with signs and symptoms of pleural TB, against an MRS? Two studies (292 participants, including 37 people with TB) assessed the accuracy of LC-mNAATs for detecting pleural TB using pleural fluid and an MRS ( Fig. 2.2.1.9). Estimated sensitivities were 48% and 75%, and estimated specificities were 89% and 96%. Due to limited data, a recommendation on using LC-mNAATs with pleural fluid for detection of pleural TB was not made. Fig. 2.2.1.9 Forest plot of LC-mNAAT sensitivity and specificity for detection of pleural TB in pleural fluid and MRS CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Should LC-mNAATs on synovial fluid be used to diagnose bone or joint TB in adults and adolescents with signs and symptoms of bone or joint TB, against an MRS? One study (five participants, including one case) assessed the accuracy of LC-mNAATs for detecting bone or joint TB using synovial fluid and an MRS (Fig. 2.2.1.10). Estimated sensitivity and specificity were both 100%. Due to limited data, a recommendation on using LC-mNAATs with synovial fluid for detection of bone or joint TB was not made. TB-LAMP for lymph node TB in lymph node biopsy Study Danfack 2024a Promsena 2022 Singh 2021 TP 26 3 4 FP 6 0 0 FN 2 0 0 TN 42 5 7 Sensitivity (95% CI) 0.93 [0.76, 0.99] 1.00 [0.29, 1.00] 1.00 [0.40, 1.00] Specificity (95% CI) 0.88 [0.75, 0.95] 1.00 [0.48, 1.00] 1.00 [0.59, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 TB-LAMP for lymph node in lymph node aspirate Study Danfack 2024a TP 2 FP 1 FN 1 TN 3 Sensitivity (95% CI) 0.67 [0.09, 0.99] Specificity (95% CI) 0.75 [0.19, 0.99] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 TB-LAMP", "for lymph node TB in lymph node pus Study Danfack 2024a TP 0 FP 2 FN 0 TN 5 Sensitivity (95% CI) Not estimable Specificity (95% CI) 0.71 [0.29, 0.96] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 TB-LAMP for pleural TB in pleural fluid Study Danfack 2024a Singh 2021 TP 14 6 FP 8 3 FN 15 2 TN 220 24 Sensitivity (95% CI) 0.48 [0.29, 0.67] 0.75 [0.35, 0.97] Specificity (95% CI) 0.96 [0.93, 0.98] 0.89 [0.71, 0.98] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 TB-LAMP for pleural TB in pleural biopsy Study Danfack 2024a TP 0 FP 22 FN 34 TN 312 Sensitivity (95% CI) 0.00 [0.00, 0.10] Specificity (95% CI) 0.93 [0.90, 0.96] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 TB-LAMP for pleural TB in pleural pus Study Danfack 2024a TP 3 FP 1 FN 0 TN 33 Sensitivity (95% CI) 1.00 [0.29, 1.00] Specificity (95% CI) 0.97 [0.85, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 44 Fig. 2.2.1.10 Forest plot of LC-mNAAT sensitivity and specificity for detection of bone or joint TB in synovial fluid and MRS CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Should LC-mNAATs on urine be used to diagnose genitourinary TB in adults and adolescents with signs and symptoms of genitourinary TB, against an MRS? One study (32 participants, including two people with TB) assessed the accuracy of LC-mNAATs for detecting genitourinary TB using urine and an MRS (Fig. 2.2.1.11). Estimated sensitivity and specificity were 50% and 100%, respectively. Due to limited data, a recommendation on using LC-mNAATs with urine for detection of genitourinary TB was not made. Fig. 2.2.1.11 Forest plot of LC-mNAAT sensitivity and specificity for detection of genitourinary TB in urine and MRS CI: confidence interval; FN: false negative; FP: false positive; LC-mNAAT: low-complexity manual nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Cost\u2013effectiveness analysis This section deals with the following additional question: What are the comparative costs, affordability and cost\u2013effectiveness of implementation of LC-mNAATs? A systematic review commissioned by WHO aimed to identify, evaluate and summarize the findings of available economic evidence on LC-mNAATs, among other technologies. The systematic review provided an in-depth analysis of the financial implications and cost\u2013 effectiveness of implementing TB LAMP in diverse settings. Through a range of economic analyses, including cost\u2013utility, cost\u2013benefit and cost\u2013affordability assessments, this study contributes valuable insights into the potential role of TB LAMP in TB diagnostics. After removing 638 duplicate studies from those identified in the original search, 1990 unique studies remained. Of these, six studies were included in the final systematic review. Studies that did not involve people with TB, used TB LAMP as a diagnostic intervention or did not contain cost data were excluded. Of the six included studies, one performed a cost\u2013utility analysis, and two performed a cost\u2013affordability analysis. The three other studies estimated the cost of TB LAMP. Study Danfack 2024a TP 1 FP 0 FN 0 TN 4 Sensitivity (95% CI) 1.00 [0.03, 1.00] Specificity (95% CI) 1.00 [0.40, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study Danfack 2024a TP 1 FP 0 FN 1 TN", "2. Recommendations for diagnosis of TB disease 45 All included studies were conducted in LMIC. Specifically, two studies were conducted in Thailand, one in Malawi, one in both Malawi and Viet Nam, and one each in India and Cameroon. The studies were conducted between 2014 and 2021 across various settings, such as outpatient departments at health centres, peripheral laboratories, a laboratory for the development of modified TB LAMP, and prisons and villages involving inmates and refugees. One study used sputum samples from people known to have TB, and another used fine needle aspiration of lymph node samples from HIV-positive patients with TB lymphadenitis. The other four studies used sputum samples from people with presumptive TB. According to the three costing studies, the cost per test ranged from US$ 1 to US$ 19 (all values in 2024 US dollars). All these studies used in-house techniques and were not using the commercially available TB LAMP test. The reviewed studies found that factors such as batching scenarios and larger test capacity influence the per-test cost, with the cost per test decreasing in specific scenarios. Testing volumes, location and operational parameters can also affect the cost. Notably, the cost\u2013utility analysis positioned TB LAMP favourably in terms of cost\u2013effectiveness compared with other diagnostic algorithms. The findings of the cost\u2013utility analysis suggested that TB LAMP, followed by DST, is not only effective but also cost-saving when compared with the standard diagnostic approach (i.e. smear, culture and DST). These results provide valuable insights for health care practitioners and policy- makers in terms of optimizing TB diagnostic strategies while considering cost\u2013effectiveness. One cost\u2013affordability analysis, conducted in peripheral laboratories in Malawi and Viet Nam, highlighted the economic considerations of implementing TB LAMP and Xpert MTB/ RIF. The study showed that per-test costs for TB LAMP were lower than those for Xpert MTB/ RIF. However, the potential financial burden of widespread implementation underscored the importance of cost\u2013effectiveness assessments in shaping diagnostic strategies. For more details see Web Annex B.9. The reviewed studies had some limitations, such as variations in settings, sample sources and comparators, which may influence the generalizability of findings. Additionally, the cost\u2013 affordability analysis underscores the financial implications of nationwide implementation, suggesting the need for careful budgetary planning and allocation. Furthermore, the Global Drug Facility\u2019s recent decrease in the price of TB LAMP (new price, US$ 6) may have an impact on the results of economic evaluations, potentially", "enhancing the cost\u2013effectiveness and affordability of implementing TB LAMP in diverse settings. These collective findings suggest that TB LAMP holds promise as a cost-effective and efficient diagnostic tool for TB when integrated into broader diagnostic algorithms, particularly in resource-constrained settings. More details on the economic evaluation of LC-mNAATs are available in Web Annex B.9. User perspective This section deals with the following question:", "WHO consolidated guidelines on tuberculosis: Fourth edition 46 Are there implications for user preferences and values, acceptability, feasibility, patient equity and human rights from the implementation of LC-mNAATs? The findings from the studies that focused on LC-aNAATs are largely applicable to LC-mNAATs, with the caveat of slightly lower sensitivity and the lack of ability to detect resistance to rifampicin. A systematic review of the qualitative evidence of LC-NAATs (Web Annex B.10) did not identify any studies focused on LC-mNAATs (acknowledging that a few studies did not specify the type of NAAT they were focusing on). However, selected findings from the interview study, did focus specifically on TB-LAMP: \u2022 In 2018, Nigeria adopted the use of TB LAMP (along with GeneXpert and Truenat). At the time of the interview, there were 199 TB LAMP machines in Nigeria. These are placed both in sites where GeneXpert is available, to decrease workload, and in peripheral laboratories where the infrastructure is insufficient to accommodate GeneXpert. Positive results from TB LAMP are sent to the nearest site with a GeneXpert or Truenat machine for DST. \u2022 The Philippines National TB Programme (NTP) guidelines advise the use of TB LAMP as an alternative primary diagnostic test in settings where access to GeneXpert is limited and that currently rely on sputum transport riders (STRiders). TB LAMP was piloted in 2019 (April to September) and 2020 (October to February 2021) in a rural health unit, polyclinic and private hospital, and for TB mass screening in a rural health unit. The pilot implementation only tested sputum with TB LAMP and did not test for TB in MDR risk groups, children or people living with HIV. According to a laboratory manager, there are about six or seven TB LAMP machines in the Philippines. These are not currently in use but could be if there was support for buying reagents. According to Nigeria\u2019s TB LAMP guidelines, the following criteria should be used to prioritize sites for TB LAMP testing: \u2022 facilities with high workload; \u2022 facilities with or without an existing molecular platform; \u2022 laboratories with adequate space and infrastructure; \u2022 availability of qualified medical laboratory personnel; \u2022 an adequate number of medical laboratory personnel; and \u2022 a storage facility (e.g. refrigerator) for laboratory and administrative supply. User preferences and values An interview study on TB LAMP involving sites in Nigeria and the Philippines found the following views of laboratory personnel", "and programme officers: \u2022 TB LAMP is making laboratory work easier over time through familiarity and because it clears the workbench; \u2022 compared to SSM, TB LAMP is easier to use; and \u2022 in direct comparison with Xpert Ultra, TB LAMP is more hands-on and requires more user steps and time for preparing and processing specimens.", "2. Recommendations for diagnosis of TB disease 47 Acceptability Acceptability of the test seems to be slightly reduced because TB LAMP cannot test for rifampicin resistance and has no multiplexing opportunities. Feasibility Summarized findings from the interview study on TB LAMP are as follows. TB LAMP improves access to TB diagnosis for people who would otherwise have been missed, because it can run in laboratories with limited infrastructure, has high throughput, is more accurate than SSM and reduces workload at GeneXpert sites. It allows decentralization of testing and therefore has the potential to reduce catastrophic cost to patients. However, TB LAMP adoption decisions are also driven by donors and investment considerations. Overall, TB LAMP allows staff to carry out more tests, and faster. Its high throughput contributes to acceptability and utilization. Laboratory staff in Nigeria are given incentives for the number of tests they carry out, making use of TB LAMP even more attractive. These incentives also support swift action when maintenance or repair of the devices is needed. Programmatic feasibility seems to be less of a concern than with GeneXpert. Compared with implementing GeneXpert, programme officers find TB LAMP more feasible to implement due to its lower requirements for infrastructure, skills level and maintenance. As with all LC-NAATs, staffing and reagent supply issues challenge its use. TB LAMP\u2019s impact on the overall turnaround time for DR-TB diagnosis, MDR-TB treatment initiation and loss to follow-up at sites without Xpert Ultra testing depends on the efficiency and robustness of the sample transport or referral system. More details on the qualitative evaluation of LC-mNAATs are available in Web Annex B.10. Implementation considerations \u2022 Diagnostic products in the low-complexity classes of tests should be prequalified by WHO or approved by another regulator before clinical use. \u2022 Diagnostic test manufacturers, laboratory and programme managers, and policy-makers should be educated on the WHO PQ process for TB IVDs. \u2022 Ensuring sufficient volume and specimen quality is important to obtain accurate results. \u2022 Safe waste disposal of used test consumables needs to be planned in advance to minimize environmental risk. Monitoring and evaluation \u2022 Track errors and invalid test result rates for currently recommended products and new products to be introduced in this class. \u2022 Monitor the proportion of people with bacteriologically confirmed TB without rifampicin- resistance reflex testing or access to further DST over time.", "WHO consolidated guidelines on tuberculosis: Fourth edition 48 Research priorities \u2022 Evaluate the performance of this class using alternative sample types for paediatric TB (e.g. gastric and nasopharyngeal aspirates, stool, induced sputum, BAL) and extrapulmonary TB. \u2022 Evaluate the impact of LC-mNAAT testing on patient-important outcomes (cure, mortality, time to diagnosis and time to start of treatment). \u2022 Evaluate the effect of sample concentration approaches (e.g. centrifugation) and volume on the performance of LC-mNAAT technologies, including in extrapulmonary TB sample types. \u2022 Evaluate the impact on incremental accuracy and case detection of alternative sample types that are easier to collect. \u2022 Develop a test in this class that can detect TB drug resistance. \u2022 Review the field performance of the current technologies used in programmatic settings. \u2022 Conduct operational research to ensure that tests are used optimally in intended settings. \u2022 Evaluate the different classes of tests, including LC-mNAATs, to determine which classes or testing strategies yield superior diagnostic accuracy, cost\u2013effectiveness and impact on equity and acceptability. \u2022 Identify an improved reference standard that accurately defines TB disease in children, paucibacillary specimens and people who cannot produce sputum, because the sensitivity of all available diagnostics is suboptimal. \u2022 Assess the budget impact and cost\u2013effectiveness of LC-mNAATs compared with other classes of tests. \u2022 Develop and apply standardized methods for assessment of costs and cost\u2013effectiveness, to improve comparability and scope of economic evidence. 2.3. Concurrent use of initial diagnostic tests for diagnosis of TB in People living with HIV and children There are significant burdens of tuberculosis in people living with HIV and children, particularly in low- and middle-income countries (LMICs). Persons living with HIV are at substantially higher risk of developing TB disease due to immunosuppression, with TB being a leading cause of death among this population. Children, especially those under five, are at high risk of progression from TB infection to TB disease and rapid disease progression and often present with broad respiratory symptoms, which complicate diagnosis and increase morbidity and mortality if not promptly treated. Addressing TB in these at-risk populations requires concerted efforts that account for their unique clinical presentations and diagnostic needs. Diagnosing TB in persons living with HIV and children is challenging, particularly because of unspecific clinical presentations and often low and varying numbers of mycobacteria in their samples that lower the sensitivity of existing diagnostic tests. Furthermore, children and people living with HIV with", "advanced immunosuppression may be unable to provide sputum samples and can have disseminated TB, which is challenging to confirm with laboratory methods. To, in part address this challenge, WHO recommends the use of stool to aid in laboratory confirmation of TB in children, and the use of urine to aid in the confirmation of TB in persons living with HIV. However, even highly sensitive tests for TB diagnosis, such as LC-aNAATs, can miss TB in these", "2. Recommendations for diagnosis of TB disease 49 groups. There is therefore a need for improved diagnostic approaches to accurately confirm TB in these higher-risk populations to ensure early and effective treatment. Tests based on the detection of the lipoarabinomannan (LAM) antigen are biomarker-based tests that may be used on urine at the point of care for TB detection. The currently available urinary LAM assay is rapid (<1 hour to result) but has suboptimal sensitivity and is therefore not suitable as general diagnostic tests for TB. However, unlike traditional diagnostic methods, it demonstrates improved sensitivity for the diagnosis of TB among individuals coinfected with HIV. The estimated sensitivity is even greater in patients with low CD4 cell counts. The lateral flow urine LAM assay (LF-LAM) strip-test \u2013 the Abbott/Alere Determine TB LAM Ag (USA), hereafter referred to as LF-LAM \u2013 is currently the only commercially available urinary LAM test. Using concurrent10 testing of different sample types offers a promising approach that considers the diagnostic testing barriers for HIV-positive adults and adolescents, HIV-positive children, and children without HIV or for whom HIV status is unknown. For instance, testing of sputum and stool during the same visit, when feasible, using LC-aNAATs increases the likelihood of detecting TB in children who may have scant bacilli in respiratory samples alone. Similarly, for persons living with HIV, testing of sputum and urine during the same visit, when sputum can be produced, using LC-aNAATs and LF-LAM increases the likelihood of detecting TB with a rapid point-of-care result while also ensuring detection of rifampicin resistance. This concurrent testing approach builds on the prior recommendation for LF-LAM test use among eligible persons living with HIV, which underscored the need for mWRD testing of available respiratory samples to support universal patient access to resistance testing services. Implementing a diagnostic approach that includes concurrent sample testing could simplify diagnostic processes, shorten the patient journey, and improve TB detection rates and health outcomes for these at-risk populations. At the same time, the inability to collect one or more specimens at the same initial visit, or lack of one of the two test types should not delay testing of available specimens and tests, but instead trigger specimen collection and testing as soon as possible. The following three scenarios of recommendations: \u2022 LC-aNAAT on respiratory samples and urine LF-LAM among adults and adolescents living with HIV \u2022 LC-aNAAT on respiratory samples and stool", "in children \u2022 LC-aNAAT on respiratory samples and stool, as well as urinary LF-LAM among children with HIV These recommendations should be implemented within recommendations for the comprehensive diagnosis and management of persons living with HIV and children. 10 Concurrent use of tests: samples are taken simultaneously (when possible), and testing is conducted for both tests. A positive result on either test is a positive result for the combination.", "WHO consolidated guidelines on tuberculosis: Fourth edition 50 2.3.1 Concurrent use of tests in people living with HIV Recommendations 7. For adults and adolescents with HIV who have signs or symptoms of TB, screen positive for TB, are seriously ill or have advanced HIV disease, concurrent testing using low-complexity automated NAATs on respiratory samples and LF-LAM on urine should be used as the initial diagnostic strategy for diagnosing TB rather than low-complexity automated NAATs on respiratory samples alone. (Strong recommendation, low certainty of evidence) Remarks \u2022 Serious illness in people living with HIV is defined based on any of the following symptoms: respiratory rate \u226530 breaths per minute, temperature \u226539 \u00b0C, heart rate \u2265120 beats per minute or unable to walk unaided. \u2022 Advanced HIV disease is defined in people living with HIV who have a CD4 cell count of <200 cells/mm3 or presenting with a WHO Stage 3/4 AIDS-defining illness. \u2022 This concurrent testing recommendation supersedes prior guidance on using LF-LAM for people living with HIV and the use of a single molecular test for diagnosis of TB in this group. \u2022 This recommendation is strong despite the low certainty of evidence because the findings indicate large desirable effects (i.e. rapid and accurate diagnosis of TB in a highly vulnerable population \u2013 people living with HIV \u2013 in whom diagnosing TB is often challenging) over small undesirable effects (i.e. negative consequences of this testing strategy). \u2022 The LC-aNAAT products for which eligible data met the class-based performance criteria for this recommendation were Xpert MTB/RIF Ultra and Truenat MTB Plus. Data for performance of Truenat MTB Plus and MTB-RIF Dx were only available for testing among persons living with HIV without concurrent LF-LAM testing. Justification and evidence In a 2016 Cochrane systematic review of the diagnostic accuracy of LF-LAM, sensitivity increased by 13% when combining LF-LAM and sputum Xpert MTB/RIF, compared with sputum Xpert alone, while the specificity decreased by 4%. However, results were based on only a few studies, and analyses were restricted to participants able to produce sputum. Incremental diagnostic accuracy In 2023, WHO commissioned a series of systematic reviews to evaluate the incremental diagnostic accuracy11 of concurrent use of either two different tests \u2013 LC-aNAAT on respiratory samples and LF-LAM on urine among people living with HIV \u2013 or the same test on two samples (LC-aNAAT on respiratory and stool samples) in children, or alternatively LC-aNAAT on", "2. Recommendations for diagnosis of TB disease 51 What is the incremental diagnostic accuracy of concurrent use of respiratory LC- aNAATs and LF-LAM on urine for diagnosis of TB disease in adults and adolescents with HIV who present with presumptive TB, compared with any of the tests alone? Of 31 studies, 27 evaluated diagnostic accuracy against an MRS, and 23 against a CRS, with 20 studies evaluating accuracy against both reference standards. A total of 27 studies (12 651 participants, including 2368 [18.7%] with TB) compared the accuracy of the concurrent use of LC-aNAAT on a respiratory sample and LF-LAM versus each of the tests alone, using an MRS. The pooled differences in sensitivity and specificity between concurrent testing versus LC-aNAAT alone were 6.7% (95% credible interval [CrI]: 3.8 to 10.7; 95% prediction interval [PI]: 0.6 to 45.9) and \u20136.8% (95% CrI: \u20139.5 to \u20134.7; 95% PI: \u201332.8 to \u20136.8), respectively (Fig. 2.3.1.1). Certainty of evidence was low for both sensitivity and specificity. A total of 23 studies (11 109 participants, including 3723 [33.5%] with TB) compared the accuracy of the concurrent use of LC-aNAAT and LF-LAM versus LC-aNAAT alone, using a CRS. The pooled differences in sensitivity and specificity between concurrent testing versus LC-aNAAT alone were 16.0% (95% CrI: 10.7 to 22.9; 95% PI: 2.3 to 60.3) and \u20133.5% (95% CrI: \u20136.6 to \u20131.7; 95% PI: \u201347.2 to \u20130.1), respectively ( Fig. 2.3.1.1). Certainty of evidence was low for sensitivity and very low for specificity. Fig. 2.3.1.1. Forest plot of pooled differences in sensitivity and specificity (all studies combined) by index test: LF-LAM, LC-aNAAT and their concurrent usea CrI: credible interval; CRS: composite reference standard; LC-aNAAT: low-complexity automated nucleic acid amplification test; LF-LAM: lateral flow urine lipoarabinomannan assay; MRS: microbiological reference standard; TB: tuberculosis. a The diamonds represent the pooled sensitivity and specificity, and the black horizontal line its 95% CrI. The pooled difference in sensitivity and specificity between concurrent testing and LC-aNAAT alone is indicated by a line connecting two diamonds. This pooled difference may not correspond to the difference between the pooled single test accuracy estimates (see Web Annex B.8). In addition to diagnostic accuracy, clinical outcome data on mortality, time to diagnosis and time to treatment were assessed. Data on cure and loss to follow-up were not assessed due to a lack of data. The data from three studies indicated that an intervention including LC-aNAAT on", "respiratory samples and LF-LAM on urine in adult inpatients with HIV was associated with slightly reduced 8-week mortality (risk ratio: 0.93; 95% CI: 0.74\u20131.17). The adjusted hazard ratio of time to diagnosis in adult inpatients with HIV was 1.55 (95% CI: 1.29\u20131.87). This means LF-LAM LCa-NAAT Concurrent Difference LF-LAM LCa-NAAT Concurrent Difference Test MRS CRS Reference 12651 12651 12651 11109 11109 11109 N 2368 (18.7%) 2368 (18.7%) 2368 (18.7%) 3723 (33.5%) 3723 (33.5%) 3723 (33.5%) No. (%) with TB 0.00 0.25 0.50 0.75 1.00 Sensitivity 39.1% (32.6 to 45.9) 68.0% (60.8 to 74.9) 77.5% (73.4 to 81.3) 6.7% (3.8 to 10.7) 38.6% (30.7 to 47.0) 46.8% (38.6 to 55.2) 67.6% (59.9 to 74.6) 16.0% (10.7 to 22.9) Summary (95% CrI) 0.00 0.25 0.50 0.75 1.00 Specificity 91.9% (88.7 to 94.4) 96.7% (95.7 to 97.6) 89.4% (85.8 to 92.3) -6.8% (-9.5 to -4.7) 96.3% (93.0 to 98.1) 99.9% (99.8 to 1) 96.2% (92.8 to 98.1) -3.5% (-6.6 to -1.7) Summary (95% CrI)", "WHO consolidated guidelines on tuberculosis: Fourth edition 52 that participants in the intervention groups (i.e. those undergoing concurrent LC-aNAAT on respiratory samples and LF-LAM on urine) were 1.55 times more likely to be diagnosed with TB within fewer days (relative reduction of 2 days and 1 day to same-day) than those in the control group. The pooled risk ratio of adult inpatients with HIV diagnosed with TB was 1.56 (95% CI: 1.29\u20131.88), indicating that the intervention group had 1.56 times the risk of being diagnosed with TB (either microbiologically confirmed or clinically diagnosed) compared with the standard of care, which included LC-aNAAT on sputum alone. The pooled risk ratio of adult inpatients with HIV with a bacteriologically confirmed TB diagnosis was 3.06 (95% CI: 1.82\u2013 5.16), indicating that the intervention group had three times the risk of being microbiologically confirmed with TB compared with the standard of care. Finally, the pooled risk ratio of adult inpatients with HIV treated for TB was 1.47 (95% CI: 1.25\u20131.73), indicating that the intervention group had 1.47 times the likelihood of being treated for TB, compared with the standard of care. Single sample testing in people living with HIV compared with the MRS Should LC-aNAATs on respiratory samples be used to diagnose pulmonary TB in PLHIV (adults and adolescents) with signs and symptoms or screened positive for pulmonary TB, against a microbiological reference standard? Twelve studies (2016 participants) evaluated sputum specimens from people living with HIV (Fig. 2.3.1.2). The sensitivities ranged between 54% and 100% and the specificities between 78% and 100%. The summary sensitivity (95% CI) was 87.4% (83.8 to 90.3) and the summary specificity was 95.2% (92.7 to 96.9). The certainty of evidence for both sensitivity and specificity were graded as \u201cHigh\u201d. Fig. 2.3.1.2 Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in PLHIV using a microbiological reference standard Studies are sorted on the plot by assay and sensitivity (low to high). FN: false negative; FP: false positive; TN: true negative; TP: true positive. Cost\u2013effectiveness analysis To date, evidence of cost\u2013effectiveness for concurrent testing is limited. Several studies have assessed Xpert MTB/RIF with LF-LAM for diagnosing TB among people living with HIV. These studies have shown that concurrent testing is likely to increase the life expectancy of people living with HIV and be cost effective compared with using Xpert MTB/RIF in sputum samples Study Theron 2024 Ngangue 2022", "Mukoka 2023 Mishra 2020a Boyles 2020 Sessolo 2023 Berhanu 2018 Dorman 2018 Ssengooba 2024 Zhang 2021 Sabi 2018 Park 2019 TP 60 60 7 17 62 29 30 103 18 24 2 1 FP 3 14 17 6 1 1 6 14 9 6 0 0 FN 10 5 6 4 13 4 4 12 2 1 0 0 TN 130 273 289 21 131 34 107 303 80 68 10 19 Brand Truenat MTB Plus Truenat MTB Plus Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Xpert Ultra Sensitivity (95% CI) 0.86 [0.75, 0.93] 0.92 [0.83, 0.97] 0.54 [0.25, 0.81] 0.81 [0.58, 0.95] 0.83 [0.72, 0.90] 0.88 [0.72, 0.97] 0.88 [0.73, 0.97] 0.90 [0.82, 0.94] 0.90 [0.68, 0.99] 0.96 [0.80, 1.00] 1.00 [0.16, 1.00] 1.00 [0.03, 1.00] Specificity (95% CI) 0.98 [0.94, 1.00] 0.95 [0.92, 0.97] 0.94 [0.91, 0.97] 0.78 [0.58, 0.91] 0.99 [0.96, 1.00] 0.97 [0.85, 1.00] 0.95 [0.89, 0.98] 0.96 [0.93, 0.98] 0.90 [0.82, 0.95] 0.92 [0.83, 0.97] 1.00 [0.69, 1.00] 1.00 [0.82, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "2. Recommendations for diagnosis of TB disease 53 alone. Fekuda et al. evaluated the cost\u2013effectiveness of concurrently using Xpert Ultra and LF-LAM among people living with HIV and concluded that concurrent testing is the preferred cost-effective strategy. Previous cost\u2013effectiveness analyses primarily focused on Xpert MTB/ RIF or Xpert Ultra, leaving a gap in evidence regarding the other technologies that may meet the LC-aNAAT class criteria. For details of particular studies see Web Annex B.9. In preparation for the GDG meeting in May 2024, WHO commissioned a study to assess the cost\u2013 effectiveness of using LC-aNAATs (including Xpert Ultra, Truenat and other novel LC-aNAATs in the development pipeline) for the detection of TB when used concurrently among people living with HIV and children, including children with HIV, across two different country settings (Malawi and the Philippines). An objective of the study was to assess the cost\u2013effectiveness of concurrent use of LC-aNAAT on respiratory samples and LF-LAM on urine for TB diagnosis and rifampicin-resistance detection among adult people living with HIV with presumptive TB, compared with a single LC-aNAAT on respiratory samples alone. In the hypothetical model, a cohort of people living with HIV with signs and symptoms of TB progressed through a decision analytical framework. In the intervention arm, TB diagnosis involved the concurrent use of LC-aNAAT on respiratory samples and LF-LAM on urine, whereas the comparator arm exclusively used LC-aNAAT on respiratory specimens. The probability of being able to provide a respiratory sample was considered, and testing was carried out, either on both respiratory and urine samples concurrently or solely on urine. In both intervention and comparator arms, participants not diagnosed through the diagnostic strategy had the opportunity for clinical diagnosis. People with bacteriologically confirmed TB underwent DST for rifampicin and began either drug-susceptible TB or DR-TB treatment, depending on the DST result. All individuals were followed over time, including those with false negative or false positive diagnostic results, to account for unnecessary treatment or additional mortality due to missed diagnoses. The cost\u2013effectiveness results of concurrent use of LC-aNAAT with LF-LAM among people living with HIV, when used in the emblematic settings of Malawi and the Philippines, are shown in Table 2.3.1.1 In Malawi, the average cost of implementing an LC-aNAAT on a respiratory sample was US$ 276, with a corresponding average DALY of 2.44. When used concurrently with LF-LAM, the average cost rose to US$ 298, while the average", "DALY decreased to 1.93. The resulting incremental cost per DALY averted was US$ 42, with a 95% uncertainty range (UR) of US$ 18 to US$ 345. Similarly, in the Philippines, LC-aNAAT on a respiratory sample had an average cost of US$ 220, with an average DALY of 2.78, whereas concurrent use with LF-LAM incurred an average cost of US$ 238 and an average DALY of 2.13. The incremental cost per DALY averted was US$ 28 (95% UR: 12\u2013249).", "WHO consolidated guidelines on tuberculosis: Fourth edition 54 Table 2.3.1.1 Cost\u2013effectiveness analysis of concurrent use of LC-aNAAT and LF-LAM among people living with HIV in Malawi and the Philippines Country Diagnostic strategy Cost, US$ Effectiveness, DALYs ICER (95% UR), US$ Malawi LC-aNAAT on respiratory sample 276 2.44 Ref LC-aNAAT on respiratory sample and LF-LAM 298 1.93 42 (18\u2013345) Philippines LC-aNAAT on respiratory sample 220 2.78 Ref LC-aNAAT on respiratory sample and LF-LAM 238 2.13 28 (12\u2013249) DALY: disability-adjusted life year; HIV: human immunodeficiency virus; ICER: incremental cost\u2013effectiveness ratio; LC-aNAAT: low-complexity automated nucleic acid amplification test; LF-LAM: lateral flow urine lipoarabinomannan assay; UR: uncertainty range. More information on the cost\u2013effectiveness analysis of concurrent use of tests in people living with HIV is available in Web Annex B.9. User perspective This section deals with the following question: Are there implications for user preferences and values, equity, acceptability, feasibility and human rights from the implementation of a concurrent testing approach (LC-aNAATs + LF-LAM)? The GDG assessed whether concurrent testing of multiple samples would increase the diagnostic accuracy (i.e. the benefit to patients or the programme in terms of finding more people with TB). Three PICO questions concerned the different concurrent sample combinations for specific groups facing challenges from reliance on respiratory samples alone (children and people living with HIV). One question focused on the concurrent use of LC-aNAAT on a respiratory sample and LF-LAM on urine for the diagnosis of TB in people living with HIV. User preferences and values As important outcomes of the diagnostic test, people in high TB burden settings value: \u2022 getting an accurate diagnosis and reaching diagnostic closure (finally knowing \u201cwhat is wrong with me\u201d); \u2022 avoiding diagnostic delays, as they exacerbate existing financial hardships and emotional and physical suffering and make people feel guilty for infecting others (especially children); \u2022 having accessible facilities; and \u2022 reducing diagnosis-associated costs (e.g. travel, missing work). More details on patient-important outcomes are available in Web Annex B.10.", "2. Recommendations for diagnosis of TB disease 55 Equity Concurrent specimen testing was not practiced in the interview study countries. However, it was believed to improve access to care by minimizing repeat visits and loss to follow-up. According to the interview study respondents, using non-sputum specimens has the potential to improve access to care, especially with a test that can be performed at all levels of the health care system. Challenges with producing a sufficient quality and quantity of sputum are well documented and can lead to repeat testing or false results. Acceptability Based on the results of the interview study, LF-LAM is being used inconsistently for people living with HIV and only for very ill patients who cannot produce sputum. Our results are in accordance with published literature on LF-LAM. Prior research on user perspectives on LF-LAM showed that it is generally described as acceptable by key stakeholders, due to its fast turnaround time, ease of use (lack of technical expertise required), low or no maintenance and equipment required, and urine being more accessible and less stigmatized than sputum. LF-LAM is deemed particularly acceptable when used in combination with other tests and clinical considerations. As the sensitivity of LF-LAM is especially low where the pretest probability is low, participants commented that it should not be used as a standalone test but should instead be used in combination with other tests, and that the results should be interpreted by a doctor considering the full clinical context, rather than being considered in isolation. Feasibility Interview study findings highlighted that the benefits of LF-LAM are crucially dependent on how several feasibility challenges are addressed. \u2022 Hygienic, safe and private sanitary facilities with running water are necessary for LF-LAM implementation at a testing site, but they are not always available, particularly in rural areas. Investments in staffing and sanitary facilities are required. \u2022 Not everybody can spontaneously produce or collect urine samples. This can be the case, for example, when the patient is too ill or septic or has to be catheterized because collecting urine samples from diapers is impossible, or if the hospital has no clean, private space to produce urine. \u2022 Visibility of faint results and result interpretation can be problematic. Comprehensive health care worker training in test interpretation (including mandatory use of the reference reading card, where appropriate) is crucial to ensure accurate result interpretation for clinical action. \u2022 The", "need for CD4 cell count results to select people for the test is problematic because these are not always immediately available. To facilitate implementation and benefit a wider range of individuals, eliminating the CD4 cell count as an eligibility criterion for people living with HIV should be considered. \u2022 In a hospital setting, bedside testing may violate patient confidentiality. \u2022 Results must be captured in a standardized way that feeds into facility and NTP reporting systems. \u2022 Quality assurance schemes need to be rolled out, and external quality controls need to be made available, to ensure tests and testing processes are quality controlled.", "WHO consolidated guidelines on tuberculosis: Fourth edition 56 Concurrent testing needs to be framed as a more efficient way of working (i.e. testing two samples concurrently during the same visit, instead of testing one sample during each of two separate visits) that also allows increasing access and reducing costs for patients. According to a laboratory manager, this framing of the benefits outweighing the additional workload, and potentially resulting in reduced work in the long run, will be critical to avoid concurrent testing being perceived as additional work for already overburdened health care workers (see Web Annex B.10). Prior investments made in frontrunner technologies, donor preferences, limited health systems thinking and unnecessary competition between manufacturers all pose challenges to policy adoption and implementation of novel molecular diagnostics. In addition, national in-country health technology and cost-efficacy assessments can delay decisions to implement newer technologies and diagnostic strategies using different samples (see Web Annex B.10). Implementation considerations \u2022 Global and national HIV and TB programmes need to communicate regularly and clearly, indicating responsibilities for concurrent testing for people living with HIV. \u2022 Concurrent testing maximizes diagnostic opportunity and accuracy of case detection, is a more efficient way to address the needs of this population and is preferred even if the testing workload may increase. \u2022 A positive result on either test is sufficient to confirm TB diagnosis. \u2022 Patient loss to follow-up for the second test result should be monitored and prevented. Patients should be provided with information to understand the concurrent testing approach and the need for follow-up. \u2022 The LF-LAM performed in point-of-care settings may be the first positive result and is sufficient to make the initial diagnosis. A respiratory sample is still required for rifampicin- resistance detection, and is also required when the LF-LAM result is negative. \u2022 Where LF-LAM is not available for testing of people living with HIV, efforts should be made to ensure access to testing. \u2022 LF-LAM does not differentiate Mtb from other mycobacterial species. However, the LAM antigen detected in a clinical sample in TB endemic areas is most likely attributable to Mtb. \u2022 When LF-LAM results are consistently positive, without positive LC-aNAAT results, investigation of the quality of testing and local epidemiology of non-tuberculosis mycobacteria and extrapulmonary TB in the tested population is warranted to understand the difference. \u2022 Interpreting bands on the LF-LAM test strip should be performed using the manufacturer\u2019s reading card", "to minimize incorrect results. \u2022 LF-LAM test strips must be stored according to the manufacturer\u2019s instructions (e.g. between 2 and 30 \u00b0C) in sealed bags and not used after expiration. \u2022 Infrastructure to collect a urine sample privately should be available. Patients should be instructed how to properly and sanitarily collect a urine sample to minimize contamination and prevent false positive results. \u2022 Trained staff will be required to perform the LF-LAM test at the point of care. \u2022 As with all WHO-recommended TB diagnostics, quality assurance programmes and quality controls for both tests are required.", "2. Recommendations for diagnosis of TB disease 57 \u2022 LF-LAM is designed to detect mycobacterial LAM antigen in human urine. Other samples (e.g. sputum, serum, plasma, CSF and other body fluids) or pooled urine specimens should not be used. Monitoring and evaluation \u2022 Monitor simultaneous specimen collection and turnaround time for the test results in a concurrent testing approach. \u2022 Monitor patient access to, and loss to follow-up from, a second test in a concurrent testing approach. \u2022 Monitor patient access to, and loss to follow-up from, follow-on DST among those with a positive LF-LAM result but a negative LC-aNAAT result. \u2022 Monitor trends in the discordance rate between the LF-LAM and LC-aNAAT results. If these differences vary from other local or regional patterns, or if the trends change, further investigation is required and outcomes should be tracked for recurrence over time. Research priorities \u2022 Conduct more rigorous studies with higher quality reference standards, including multiple specimen types and extrapulmonary samples, to improve confidence in specificity estimates. \u2022 Gather evidence on the impact of concurrent testing on TB treatment initiation and mortality. \u2022 Determine training, competency and quality assessment needs by setting and by cadre of staff (i.e. health care worker, laboratory technician or clinical staff). \u2022 Perform country-specific cost\u2013effectiveness and cost\u2013benefit analyses of the concurrent testing approaches or sequential testing approaches in different programmatic settings. \u2022 Develop and apply standardized methods for assessment of costs and cost\u2013effectiveness, to improve comparability and scope of economic evidence. \u2022 Perform operational research on availability, requirements and best practices for the point- of-care set-up: private specimen collection facility, tabletop space for testing samples, and reporting system (preferably digital) for entry of results, with linkages to existing information management systems (i.e. health and laboratory information management systems). 2.3.2 Concurrent use of tests in children without HIV or with unknown HIV status Recommendations 8. For children who are HIV-negative or have an unknown HIV status, who have signs or symptoms or screen positive for pulmonary TB, concurrent testing using low-complexity automated NAATs on respiratory and stool samples should be used as the initial diagnostic strategy for diagnosing TB rather than low- complexity automated NAATs on respiratory or stool samples alone. (Strong recommendation, low certainty of evidence for test accuracy) NEW", "WHO consolidated guidelines on tuberculosis: Fourth edition 58 Remarks \u2022 This recommendation prioritizes concurrent testing of two different sample types over the use of a single molecular test for diagnosis of TB in children. \u2022 Use of LC-aNAATs on isolated specimens was also evaluated. The findings supported the use of LC-aNAATs for initial diagnostic testing for TB in children with signs or symptoms or who screen positive for pulmonary TB, using respiratory sample, gastric aspirate, stool or nasopharyngeal aspirate, rather than smear or culture. \u2022 This recommendation is strong despite the low certainty of evidence because the findings indicate large desirable effects (i.e. rapid and accurate diagnosis of TB in a highly vulnerable population \u2013 children \u2013 in whom diagnosing TB is often challenging) over trivial undesirable effects (i.e. negative consequences of this testing strategy) (for more details, see GRADE evidence to decision [EtD] table, Web Annex A.4). \u2022 The product for which eligible data met the LC-aNAAT class-based performance criteria for this recommendation was Xpert MTB/RIF Ultra. The performance of Truenat MTB Plus and MTB-RIF Dx for this recommendation could not be assessed, as data were unavailable. Justification and evidence LC-aNAATs on respiratory and stool samples are recommended as the first test for symptomatic children presenting with presumptive TB disease, and are widely used to diagnose TB. Previous systematic reviews have traditionally assessed diagnostic accuracy of LC-aNAATs on two samples in isolation for the detection of TB in children, but in clinical practice the tests may be used concurrently (i.e. LC-aNAAT on a respiratory sample and a stool sample) and together they increase sensitivity. Incremental diagnostic accuracy of concurrent testing compared with single sample testing What is the incremental diagnostic accuracy of concurrent use of LC-aNAATs on respiratory and stool samples for diagnosis of pulmonary TB disease in children who are HIV-negative or have an unknown HIV status, with signs and symptoms or who screened positive for pulmonary TB, compared with use of an LC-aNAAT on one sample type (either respiratory or stool)? Eight studies (2145 participants, 173 [8.1%] of whom had TB disease) compared the accuracy of concurrent use of LC-aNAATs with respiratory and stool samples (LC-aNAATs combined) versus LC-aNAAT on one sample type (either respiratory or stool) against an MRS. Compared with LC-aNAAT on respiratory samples alone, concurrent testing had 7.1 percentage points (95% CrI: 3.2 to 13.4) higher sensitivity and \u20131.7 percentage points (95% CrI: \u20133.8", "to \u20130.6) lower specificity. Certainty of evidence for both sensitivity and specificity was low for comparison with LC-aNAAT on respiratory samples alone. Compared with LC-aNAAT on stool alone, concurrent testing had 22.1 percentage points (95% CrI: 13.7 to 32.7) higher sensitivity and \u20134.1 percentage points (95% CrI: \u20138.0 to \u20131.7) lower specificity. Certainty of evidence was moderate for sensitivity and low for specificity for comparison with LC-aNAAT on stool alone.", "2. Recommendations for diagnosis of TB disease 59 Twelve studies (3579 participants, 1464 [40.9%] of whom had TB disease) compared the accuracy of LC-aNAATs combined versus each LC-aNAAT alone against a CRS. Compared with LC-aNAAT on respiratory samples alone, concurrent testing had 4.7 percentage points (95% CrI: 2.1 to 8.9) higher sensitivity and \u20130.5 percentage points (95% CrI: \u20131.4 to 0) lower specificity. Compared with LC-aNAAT on stool alone, concurrent testing had 10.5 percentage points (95% CrI: 6.9 to 15.0) higher sensitivity and \u20130.1 percentage points (95% CrI: \u20130.7 to \u20130.005) lower specificity. Certainty of evidence was very low for both sensitivity and specificity for both comparisons (concurrent testing versus respiratory sample alone and stool alone) under a CRS ( Fig. 2.3.2.1). The data on Truenat MTB Plus and MTB-RIF Dx were unavailable. Fig. 2.3.2.1 Forest plot of pooled sensitivity and specificity for all studies, by each index test CrI: credible interval; CRS: composite reference standard; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis. The diamonds represent pooled sensitivity and specificity, and the black horizontal line its 95% CrI. The difference in accuracy between index tests is indicated by solid lines (concurrent versus stool) or dotted lines (concurrent versus respiratory) connecting the diamonds. Single sample testing in children compared with the MRS Should LC-aNAATs on respiratory samples be used to diagnose pulmonary TB in children with signs and symptoms or who screened positive for pulmonary TB, against an MRS? Fifteen studies (3024 participants) evaluating sputum were identified, with sensitivities ranging between 57% and 91% and specificities between 82% and 100% (Fig. 2.3.2.2). Eleven studies (2990 participants) were included in the meta-analysis. The summary sensitivity was 75.3% (95% CI: 68.9\u201380.8) and summary specificity was 95.9% (95% CI: 92.3\u201397.9). Certainty of evidence was high for both sensitivity and specificity. The data on Truenat MTB Plus and MTB- RIF Dx were unavailable. LC-aNAAT stool LC-aNAAT resp Concurrent \u0394 Concurrent vs. resp \u0394 Concurrent vs. stool LC-aNAAT stool LC-aNAAT resp Concurrent \u0394 Concurrent vs. resp \u0394 Concurrent vs. stool Test MRS CRS Reference 2145 2145 2145 3579 3579 3573 N 173 (8.07%) 173 (8.07%) 173 (8.07%) 1513 (42.3%) 1513 (42.3%) 1507 (42.2%) No. (%) with TB 0.00 0.25 0.50 0.75 1.00 Sensitivity 56.3% (42.9 to 69.9) 72.6% (59.0 to 84.6) 79.9% (67.8 to 89.8) 7.1% (3.2 to 13.4) 22.1% (13.7 to 32.7) 16.4% (8.4 to 29.4) 21.7% (12.9 to", "34.4) 29.0% (17.3 to 44.7) 4.7% (2.1 to 8.9) 10.5% (6.9 to 15.0) Summary (95% CrI) 0.00 0.25 0.50 0.75 1.00 Specificity 97.5% (94.8 to 99) 95% (90.6 to 97.7) 93.4% (87.2 to 97) -1.7% (-3.8 to -0.6) -4.1% (-8.0 to -1.7) 99.3% (97.8 to 99.8) 99.7% (97.9 to 1) 99.1% (96.1 to 99.8) -0.5% (-1.4 to -0.1) -0.1% (-0.7 to -0.005) Summary (95% CrI)", "WHO consolidated guidelines on tuberculosis: Fourth edition 60 Fig. 2.3.2.2 Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in sputum samples and MRS CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Should LC-aNAATs on gastric aspirate specimens be used to diagnose pulmonary TB in children with signs and symptoms or who screened positive for pulmonary TB, against an MRS? Twelve studies (1959 participants) were identified, with sensitivities between 0% and 100% and specificities between 67% and 100% ( Fig. 2.3.2.3). All 12 studies were included in the meta-analysis. The summary sensitivity was 69.6% (95% CI: 60.3\u201377.6) and summary specificity was 91.0% (95% CI: 82.5\u201395.6). Certainty of evidence was moderate for both sensitivity and specificity. The data on Truenat MTB Plus and MTB-RIF Dx were unavailable. Fig. 2.3.2.3 Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in gastric aspirate and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted on the plot by decreasing sensitivity and specificity. Study Aguilera-Alonso 2022 Barcellini 2019 Liu 2021 NCT04121026 Yenew 2023 Enimill 2022 Zar 2018-2023 Kabir 2020 Jaganath 2021 NCT03734172 Nicol 2018 NCT04899076 Sabi 2022 Ssengooba 2020 Sabi 2018 TP 0 0 0 0 10 35 89 4 7 38 47 5 17 2 12 FP 0 0 1 0 0 16 66 18 1 36 9 7 10 3 0 FN 0 0 0 0 1 7 19 1 2 11 18 2 8 1 9 TN 1 1 6 25 93 71 499 379 71 519 261 56 340 68 122 Sensitivity (95% CI) Not estimable Not estimable Not estimable Not estimable 0.91 [0.59, 1.00] 0.83 [0.69, 0.93] 0.82 [0.74, 0.89] 0.80 [0.28, 0.99] 0.78 [0.40, 0.97] 0.78 [0.63, 0.88] 0.72 [0.60, 0.83] 0.71 [0.29, 0.96] 0.68 [0.46, 0.85] 0.67 [0.09, 0.99] 0.57 [0.34, 0.78] Specificity (95% CI) 1.00 [0.03, 1.00] 1.00 [0.03, 1.00] 0.86 [0.42, 1.00] 1.00 [0.86, 1.00] 1.00 [0.96, 1.00] 0.82 [0.72, 0.89] 0.88 [0.85, 0.91] 0.95 [0.93, 0.97] 0.99 [0.93, 1.00] 0.94 [0.91, 0.95] 0.97 [0.94, 0.98] 0.89 [0.78, 0.95] 0.97 [0.95, 0.99] 0.96 [0.88, 0.99] 1.00 [0.97, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8", "1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study NCT04899076 NCT04121026 Aguilera-Alonso 2022 Parigi 2021 Yenew 2023 NCT03734172 Liu 2021 NCT04240990 Ssengooba 2020 Enimill 2022 Sabi 2022 Jaganath 2021 TP 1 4 19 13 31 3 18 9 11 2 6 0 FP 6 0 10 5 8 6 9 25 12 2 6 3 FN 0 0 4 3 9 1 7 7 9 2 7 1 TN 13 137 33 16 632 24 46 504 212 4 56 23 Sensitivity (95% CI) 1.00 [0.03, 1.00] 1.00 [0.40, 1.00] 0.83 [0.61, 0.95] 0.81 [0.54, 0.96] 0.78 [0.62, 0.89] 0.75 [0.19, 0.99] 0.72 [0.51, 0.88] 0.56 [0.30, 0.80] 0.55 [0.32, 0.77] 0.50 [0.07, 0.93] 0.46 [0.19, 0.75] 0.00 [0.00, 0.97] Specificity (95% CI) 0.68 [0.43, 0.87] 1.00 [0.97, 1.00] 0.77 [0.61, 0.88] 0.76 [0.53, 0.92] 0.99 [0.98, 0.99] 0.80 [0.61, 0.92] 0.84 [0.71, 0.92] 0.95 [0.93, 0.97] 0.95 [0.91, 0.97] 0.67 [0.22, 0.96] 0.90 [0.80, 0.96] 0.88 [0.70, 0.98] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "2. Recommendations for diagnosis of TB disease 61 Should LC-aNAATs on nasopharyngeal aspirate specimens be used to diagnose pulmonary TB in children with signs and symptoms or who screened positive for pulmonary TB, against an MRS? Seven studies (1355 participants) were identified, with sensitivities between 33% and 67% and specificities between 50% and 99% (Fig. 2.3.2.4). Six studies (1353) were included in the meta-analysis. The summary sensitivity was 46.2% (95% CI: 34.9\u201357.9) and summary specificity was 97.5% (95% CI: 95.1\u201398.7). Certainty of evidence was moderate for sensitivity and high for specificity. The data on Truenat MTB Plus and MTB-RIF Dx were unavailable. Fig. 2.3.2.4 Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in nasopharyngeal aspirate samples and MRS CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test; MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. Should LC-aNAATs on stool be used to diagnose pulmonary TB in children with signs and symptoms or who screened positive for pulmonary TB, against an MRS? Ten studies (2855 participants) were identified, with sensitivities between 26% and 100% and specificities between 89% and 100% (Fig. 2.3.2.5). All 10 studies were included in the meta- analysis. The summary sensitivity was 68.0% (95% CI: 50.3\u201381.7) and summary specificity was 98.2% (95% CI: 96.3 to 99.1). Certainty of evidence was moderate for sensitivity and high for specificity. The data on Truenat MTB Plus and MTB-RIF Dx were unavailable. Fig. 2.3.2.5 Forest plot of LC-aNAAT sensitivity and specificity for detection of pulmonary TB in stool and MRSa CI: confidence interval; FN: false negative; FP: false positive; LC-aNAAT: low-complexity automated nucleic acid amplification test: MRS: microbiological reference standard; TB: tuberculosis; TN: true negative; TP: true positive. a Studies are sorted on the plot by decreasing sensitivity. Study Liu 2021 NCT04121026 NCT04899076 Jaganath 2021 Zar 2018-2023 NCT03734172 NCT04240990 TP 0 2 2 2 16 15 5 FP 1 6 7 2 4 5 3 FN 0 1 2 2 19 18 10 TN 1 154 115 20 151 280 512 Sensitivity (95% CI) Not estimable 0.67 [0.09, 0.99] 0.50 [0.07, 0.93] 0.50 [0.07, 0.93] 0.46 [0.29, 0.63] 0.45 [0.28, 0.64] 0.33 [0.12, 0.62] Specificity (95% CI) 0.50 [0.01, 0.99] 0.96 [0.92, 0.99] 0.94 [0.89, 0.98] 0.91 [0.71, 0.99] 0.97 [0.94, 0.99] 0.98 [0.96, 0.99] 0.99 [0.98, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1", "Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1 Study NCT04121026 NCT04203628 Babo 2023 de Haas 2022 Chibolela 2023 Yenew 2023 Liu 2021 Kabir 2020 NCT04240990 NCT04899076 TP 3 3 15 22 10 41 28 11 9 11 FP 4 0 7 6 1 4 4 40 4 1 FN 0 0 2 4 2 19 20 12 12 31 TN 135 71 285 192 101 716 57 339 518 145 Sensitivity (95% CI) 1.00 [0.29, 1.00] 1.00 [0.29, 1.00] 0.88 [0.64, 0.99] 0.85 [0.65, 0.96] 0.83 [0.52, 0.98] 0.68 [0.55, 0.80] 0.58 [0.43, 0.72] 0.48 [0.27, 0.69] 0.43 [0.22, 0.66] 0.26 [0.14, 0.42] Specificity (95% CI) 0.97 [0.93, 0.99] 1.00 [0.95, 1.00] 0.98 [0.95, 0.99] 0.97 [0.94, 0.99] 0.99 [0.95, 1.00] 0.99 [0.99, 1.00] 0.93 [0.84, 0.98] 0.89 [0.86, 0.92] 0.99 [0.98, 1.00] 0.99 [0.96, 1.00] Sensitivity (95% CI) 0 0.2 0.4 0.6 0.8 1 Specificity (95% CI) 0 0.2 0.4 0.6 0.8 1", "WHO consolidated guidelines on tuberculosis: Fourth edition 62 Cost\u2013effectiveness analysis As part of the preparatory process for the GDG meeting in May 2024, WHO commissioned a modelled study to assess the cost\u2013effectiveness of using LC-aNAATs (including Xpert Ultra, Truenat and other novel LC-aNAATs in the development pipeline) for the detection of TB when used concurrently among people living with HIV and children, including children with HIV, across two different country settings (Malawi and the Philippines). A study objective was to assess the cost\u2013effectiveness of concurrent use of LC-aNAATs on respiratory and stool samples for TB diagnosis and rifampicin-resistance detection among children (aged <10 years) with presumptive TB and without HIV infection, compared with a single LC-aNAAT on a respiratory sample alone. In this hypothetical model, a cohort of children with presumptive TB progressed through a decision analytical framework. In the intervention arm, TB diagnosis involved the concurrent use of LC-aNAATs on both respiratory and stool samples, whereas the comparator arm solely used LC-aNAATs on respiratory specimens. The probability of being able to provide a respiratory sample was considered, and testing was conducted, either for both respiratory and stool samples concurrently or solely for stool. In both the intervention and comparator arms, participants not diagnosed through the diagnostic strategy had the opportunity for clinical diagnosis. Children with bacteriologically confirmed TB underwent DST for rifampicin and began either drug- susceptible TB or DR-TB treatment, depending on the DST result. All individuals were followed over time, including those with false negative or false positive diagnostic results, to account for unnecessary treatment or additional mortality due to missed diagnoses. When using the high TB burden setting of Malawi to parametrize the model, cost\u2013effectiveness modelling found that the use of an LC-aNAAT on a respiratory sample resulted in an average cost of US$ 144, with a corresponding average DALY of 0.93. In contrast, the concurrent use of LC-aNAATs on respiratory and stool samples yielded an average cost of US$ 204, and a DALY of 0.57, resulting in an incremental cost per DALY averted of US$ 253 (95% UR: 123\u20132317) (Table 2.3.2.1). Similarly, in the Philippines, the cost of an LC-aNAAT on a respiratory sample was US$ 84, associated with a DALY of 1.04. Concurrent testing in the Philippines resulted in an average cost of US$ 149 and a DALY of 0.66, with an ICER of US$ 156 per DALY averted (95% UR: 79\u2013888) (Table 2.3.2.1).", "2. Recommendations for diagnosis of TB disease 63 Table 2.3.2.1 Cost\u2013effectiveness analysis of concurrent use of LC-aNAATs among children in Malawi and the Philippines Country Diagnostic strategy Cost, US$ Effectiveness, DALYs ICER (95% UR), US$ Malawi LC-aNAAT on respiratory sample 114 0.93 Reference LC-aNAATs on respiratory and stool samples 204 0.57 253 (123\u20132317) Philippines LC-aNAAT on respiratory sample 84 1.04 Reference LC-aNAATs on respiratory and stool samples 149 0.62 156 (79\u2013888) DALY: disability-adjusted life year; ICER: incremental cost\u2013effectiveness ratio; LC-aNAAT: low-complexity automated nucleic acid amplification test; UR: uncertainty range. More information on the cost\u2013effectiveness analysis of concurrent use of tests in children is available in Web Annex B.9. User perspective The GDG assessed whether concurrent testing of multiple samples would increase the diagnostic yield (i.e. the benefit to patients or the programme in terms of finding more people with TB). One of the PICO questions focused on the concurrent use of LC-aNAATs on respiratory and stool samples for the diagnosis of TB in children. User preferences and values As important outcomes of the diagnostic test, people in high TB burden settings value: \u2022 getting an accurate diagnosis and reaching diagnostic closure (finally knowing \u201cwhat is wrong with me\u201d); \u2022 avoiding diagnostic delays, as they exacerbate existing financial hardships and emotional and physical suffering and make people feel guilty for infecting others (especially children); \u2022 having accessible facilities; and \u2022 reducing diagnosis-associated costs (e.g. travel, missing work). Participants appreciate that stool collection is far less invasive than gastric lavage and can thereby reduce physical and emotional suffering of children and their parents (see Web Annex B.10). Equity Concurrent specimen testing was not practiced in the interview study countries. However, it was believed to improve access to care by minimizing repeat visits and loss to follow-up. According to the interview study respondents, using non-sputum specimens has the potential to improve access to care, especially with a test that can be performed at all levels of the health", "WHO consolidated guidelines on tuberculosis: Fourth edition 64 care system. Challenges with producing a sufficient quality and quantity of sputum are well documented and can lead to repeat testing or false results. Acceptability Most participants, including health workers and caregivers, did not immediately understand why multiple samples would be tested concurrently at the same visit, if a respiratory sample is available. They highlighted that a sputum sample is the preferred choice, and they would only collect the second-best sample if that were not available. However, participants also thought that concurrent sample testing could be possible if there was a WHO recommendation, altered diagnostic algorithms and specific training and capacity strengthening to facilitate it (see Web Annex B.10). For young children, stool seems to be an acceptable specimen, especially after adequate training in how to process it. Stool from adults is considered more difficult in terms of both acceptance and processing time. In general, participants had confidence in the results from stool tested by GeneXpert (see Web Annex B.10). Feasibility Important feasibility challenges are related to the deteriorating quality of stool, caused by delays between time of collection and time of processing in the laboratory (see Web Annex B.10). Concurrent testing needs to be framed as a more efficient way of working (i.e. testing two samples concurrently during the same visit, instead of testing one sample during each of two separate visits) that also allows increasing access and reducing costs for patients. The practice of concurrent testing needs to be framed as generating sufficient benefit to justify the additional short-term workload and having the potential to reduce the workload in the longer term. Without such framing, there is a risk that already overburdened health care workers will avoid concurrent testing (see Web Annex B.10). Prior investments made in frontrunner technologies, donor preferences, limited health systems thinking and unnecessary competition between manufacturers all pose challenges to policy adoption and implementation of novel molecular diagnostics. In addition, national in-country health technology and cost-efficacy assessments can delay decisions to implement newer technologies and diagnostic strategies using different samples (see Web Annex B.10). More information on the qualitative evidence analysis and synthesis for concurrent use of tests in children is available from Web Annex B.10. Implementation considerations \u2022 Concurrent testing maximizes diagnostic opportunity and accuracy of case detection, is a more efficient way to address the needs of this population and is preferred even if", "2. Recommendations for diagnosis of TB disease 65 \u2022 Testing capacity should be secured for the second test, as volumes will increase. \u2022 Adequate staffing capacity and training are needed to improve the collection of different sample types and laboratory processing of collected samples. \u2022 Performing the same test on a new sample may need additional regulatory approval on a national and international level. \u2022 Infrastructure and training on how to collect a stool sample privately should be available. \u2022 As with all WHO-recommended TB diagnostics, quality assurance programmes for both sample types are required. \u2022 At a primary health care level, in a situation of sputum paucity or absence, stool and nasopharyngeal aspirate may be feasible, whereas collection of more invasive specimen types (i.e. induced sputum, BAL and gastric aspirate) would require upward referral, depending local capacity and expertise. In these circumstances, performing stool testing at primary health care level and waiting for a test result before upward referral of the child may be appropriate. Monitoring and evaluation \u2022 Monitor simultaneous specimen collection and turnaround time for the test results in a concurrent testing approach. \u2022 Monitor patient loss to follow-up from a second test in a concurrent testing approach. \u2022 Monitor trends in the rate of indeterminate test results for both sample types with LC-aNAATs. \u2022 Monitor trends in the discordance rate between the respiratory and stool LC-aNAAT results. If these differences vary from other local or regional patterns, or if the trends change, further investigation is required. Research priorities \u2022 Evaluate the impact of concurrent specimen testing on patient-important outcomes for children (cure, mortality, time to diagnosis and time to start of treatment). \u2022 Evaluate the impact of concurrent specimen testing on affordability and cost\u2013effectiveness in the intended settings of use. \u2022 Evaluate the performance of other LC-aNAATs in concurrent testing approaches. \u2022 Identify an improved reference standard that accurately defines TB disease in children and paucibacillary specimens because the sensitivity of all available diagnostics is suboptimal. \u2022 Develop new tools that correctly diagnose a higher proportion of TB in children. Ideally, the new tools will be rapid, affordable, feasible and acceptable to children and their parents. \u2022 Develop rapid point-of-care diagnostic tests and simpler alternative sample types for paucibacillary and extrapulmonary TB in children. \u2022 Perform operational research to ensure that tests are used optimally in intended settings. \u2022 Develop and apply standardized methods for assessment", "WHO consolidated guidelines on tuberculosis: Fourth edition 66 2.3.3 Concurrent use of tests in children with HIV Recommendations 9. For children with HIV who have signs or symptoms or screen positive for pulmonary TB, concurrent testing using low-complexity automated NAATs on respiratory and stool samples and LF-LAM on urine may be used as the initial diagnostic strategy for diagnosing TB rather than low-complexity automated NAATs on respiratory or stool samples alone. (Conditional recommendation, low certainty of evidence for test accuracy) Remarks \u2022 This recommendation prioritizes concurrent testing over the use of molecular testing and LF-LAM in isolation for diagnosis of TB in children with HIV. \u2022 Use of LC-aNAATs on isolated specimens was also evaluated. The findings supported the use of LC-aNAATs for initial diagnostic testing for TB in HIV-positive children with signs or symptoms or who screen positive for pulmonary TB, using sputum, gastric aspirate, stool or nasopharyngeal aspirate, rather than smear or culture. \u2022 This recommendation is conditional because the findings indicate moderate undesirable effects (i.e. decreased specificity, resulting in more false positive test results) when compared with a single test strategy. \u2022 The product for which eligible data met the LC-aNAAT class-based performance criteria for this recommendation was Xpert MTB/RIF Ultra. The performance of Truenat MTB Plus and MTB-RIF Dx for this recommendation could not be assessed, as data were unavailable. Justification and evidence LC-aNAATs on respiratory and stool sample and LF-LAM on urine are recommended as the first test for symptomatic children with HIV presenting with presumptive TB disease, and should be used to diagnose TB. Previous systematic reviews have traditionally assessed diagnostic accuracy of LC-aNAATs on two samples and LF-LAM on urine in isolation for the detection of TB in children, but in clinical practice the tests may be used concurrently (i.e. LC-aNAAT on a respiratory and stool sample and LF-LAM on urine) and together they increase sensitivity. Incremental diagnostic accuracy What is the incremental diagnostic accuracy of concurrent use of LC-aNAATs on respiratory and stool samples and LF-LAM on urine versus each sample type alone for diagnosis of pulmonary TB disease in children with HIV, with signs and symptoms or who screened positive for pulmonary TB, compared with any of the tests (either LC-aNAATs combined or LF-LAM) alone? Based on six studies (653 participants, including 43 [6.6%] with TB) included in the meta-analysis for an MRS, the estimated diagnostic accuracy of the concurrent use", "2. Recommendations for diagnosis of TB disease 67 samples plus LC-aNAAT on stool and LF-LAM on urine had a pooled sensitivity of 77.8% (95% CrI: 59.9 to 89.8) and a pooled specificity of 83.9% (95% CrI: 73.9 to 90.4) (Fig. 2.3.7). Compared with LC-aNAAT on respiratory samples alone, concurrent testing had 6.9 percentage points (95% CrI: 1.5 to 20.1) higher sensitivity and \u201310.1 percentage points (95% CrI: \u201321.6 to \u20134.9) lower specificity. Certainty of evidence was low for specificity and moderate for sensitivity. Based on six studies (674 participants, including 286 [42.4%] with TB) included in the meta- analysis for a CRS, the estimated diagnostic accuracy of the concurrent use of LC-aNAAT on respiratory samples plus LC-aNAAT on stool and LF-LAM on urine had a pooled sensitivity of 30.1% (95% CrI: 13.2 to 54.9) and a pooled specificity of 83.3% (95% CrI: 69.6 to 90.2) (Fig. 2.3.3.1). Compared with LC-aNAAT on respiratory samples alone, concurrent testing had 14.9 percentage points (95% CrI: 0 to 41.1) higher sensitivity and \u201312.0 percentage points (95% CrI: \u201327.0 to \u20132.6) lower specificity. Certainty of evidence was very low for sensitivity and low for specificity. Fig. 2.3.3.1 Forest plot of pooled sensitivity and specificity for all studies, by each index test CrI: credible interval; CRS: composite reference standard; LC-aNAAT: low-complexity automated nucleic acid amplification test; LF-LAM: lateral flow urine lipoarabinomannan assay; MRS: microbiological reference standard; TB: tuberculosis. a The diamonds represent pooled sensitivity and specificity, and the black horizontal line its 95% CrI. The difference in accuracy between index tests is indicated by solid lines (concurrent versus stool) or dotted lines (concurrent versus respiratory) connecting the diamonds. Cost\u2013effectiveness analysis In addition to the economic evidence regarding concurrent use of tests in people living with HIV and children (see Sections 2.3.1 and 2.3.2), WHO commissioned a third study that aimed to assess the cost\u2013effectiveness of using LC-aNAATs (including Xpert Ultra, Truenat and other novel LC-aNAATs in the development pipeline) for the detection of TB when used concurrently among children with HIV, across two different country settings (Malawi and the Philippines). An objective of this study was to assess the cost\u2013effectiveness of concurrent use of LC-aNAATs on respiratory and stool samples and LF-LAM on urine for TB diagnosis and rifampicin-resistance LF-LAM Combined LC-aNAATs Concurrent \u0394 Concurrent vs. comb. LC-aNAATs \u0394 Concurrent vs. LF-LAM LF-LAM Combined LC-aNAATs Concurrent \u0394 Concurrent vs. comb. LC-aNAATs \u0394 Concurrent vs. LF-LAM Test", "MRS CRS Reference 653 653 653 674 674 674 N 43 (6.6%) 43 (6.6%) 43 (6.6%) 286 (42.4%) 286 (42.4%) 286 (42.4%) No. (%) with TB 0.00 0.25 0.50 0.75 1.00 Sensitivity 27.4% (13.5 to 47.5) 69.3% (49.9 to 84) 77.6% (60 to 89.6) 6.9% (1.5 to 20.1) 49.9% (30.7 to 68.8) 17.7% (7.6 to 35.4) 14.8% (6.8 to 27.8) 30% (13.2 to 54.8) 11.5% (3.8 to 26.7) 10.1% (5.1 to 17.7) Summary (95% CrI) 0.00 0.25 0.50 0.75 1.00 Specificity 88.2% (78.2 to 93.8) 95.4% (91.1 to 98) 83.9% (73.9 to 90.4) -10.2% (-19.6 to -4.9) -3.4% (-6.9 to -1.3) 88.7% (76.4 to 94.1) 95.5% (88.6 to 98.4) 83.3% (69.8 to 90.2) -10.1% (-21.6 to -4.9) -3.5% (-8.8 to -1.1) Summary (95% CrI)", "WHO consolidated guidelines on tuberculosis: Fourth edition 68 detection among children (aged <10 years) living with HIV and with presumptive TB, compared with a single LC-aNAAT on a respiratory sample alone. In the hypothetical model that informed this study, a cohort of children with HIV and with signs and symptoms of TB progressed through a decision analytical framework. In the intervention arm, TB diagnosis involved the concurrent use of LC-aNAATs on both respiratory and stool samples, alongside LF-LAM on urine. The comparator arm used LC-aNAAT on respiratory samples alone. The probability of providing a respiratory sample was considered, and testing was conducted, either concurrently on respiratory and stool samples alongside LF-LAM, or on stool alone alongside LF-LAM. In both the intervention and comparator arm, participants not diagnosed through the diagnostic strategy had the opportunity for clinical diagnosis. Children with bacteriologically confirmed TB underwent DST for rifampicin and began either drug- susceptible TB or DR-TB treatment, depending on the DST result. All individuals were followed over time, including those with false negative or false positive diagnostic results, to account for unnecessary treatment or additional mortality due to missed diagnoses. The study findings shown in Table 2.3.3.1 show the cost\u2013effectiveness of the concurrent use of LC-aNAATs on respiratory and stool samples and LF-LAM on urine among children with HIV in Malawi and the Philippines. In Malawi, the average cost of implementing an LC-aNAAT on a respiratory sample was US$ 319, with a corresponding average DALY of 5.08. When used concurrently, the average cost increased to US$ 460, while the average DALY decreased to 1.8. The resulting ICER per DALY averted was US$ 43 (95% UR: 28\u201389). Similarly, in the Philippines, implementation of an LC-aNAAT on a respiratory sample alone cost US$ 249, with an average DALY of 5.13, whereas concurrent use incurred an average cost of US$ 345 and an average DALY of 1.77. The ICER per DALY averted was US$ 29 (95% UR: 18\u201363). Table 2.3.3.1 Cost\u2013effectiveness analysis of concurrent use of LC-aNAATs among children living with HIV in Malawi and the Philippines Country Diagnostic strategy Cost, US$ Effectiveness, DALYs ICER (95% UR), US$ Malawi LC-aNAAT on respiratory sample 320 5.08 Reference LC-aNAAT on respiratory and stool samples and LF-LAM 460 1.8 43 (28\u201389) Philippines LC-aNAAT on respiratory sample 249 5.13 Reference LC-aNAAT on respiratory and stool samples and LF-LAM 345 1.77 29 (18\u201363) DALY: disability-adjusted life year; HIV: human immunodeficiency", "2. Recommendations for diagnosis of TB disease 69 User perspective The GDG assessed whether concurrent testing of multiple samples would increase the diagnostic yield (i.e. the benefit to patients or the programme in terms of finding more people with TB). One of the PICO questions focused on concurrent use of LC-aNAATs on respiratory and stool samples and LF-LAM on urine for the diagnosis of TB in children living with HIV. User preferences and values The interview study and quality evidence synthesis produced no data on the use of LF-LAM in children living with HIV. However, in general, as important outcomes of the diagnostic test, patients in high TB burden settings value: \u2022 getting an accurate diagnosis and reaching diagnostic closure (finally knowing \u201cwhat is wrong with me\u201d); \u2022 avoiding diagnostic delays, as they exacerbate existing financial hardships and emotional and physical suffering and make people feel guilty for infecting others (especially children); \u2022 having accessible facilities; and \u2022 reducing diagnosis-associated costs (e.g. travel, missing work). Participants appreciate that stool sample collection is far less invasive than gastric aspirate (see Web Annex B.10). Equity Concurrent sample testing was not practiced in the study countries. However, concurrent sample testing could improve access to care by minimizing repeat visits and loss to follow-up (see Web Annex B.10). Using non-sputum samples can improve access to care, especially with a test that can be performed at all levels of the health carecare system. Challenges with producing sputum of sufficient quality and quantity are well documented and can lead to repeat testing or false results. Participants highlighted the impact that using stool has on increasing case-finding and access to care, particularly among destitute families (see Web Annex B.10). Acceptability The interview study produced no data on the use of LF-LAM in children living with HIV. Most participants (including parents and legal representatives of children) did not immediately understand why multiple samples would be tested concurrently at the same visit, if a respiratory sample is available. They highlighted that a sputum sample is the preferred choice, and they would only collect the second-best sample if that were not available. However, participants also thought that concurrent sample testing could be possible if there was a WHO recommendation, altered diagnostic algorithms and specific training and capacity strengthening to facilitate it (see Web Annex B.10). For young children, stool seems to be an acceptable specimen, especially after adequate training in", "WHO consolidated guidelines on tuberculosis: Fourth edition 70 Feasibility The interview study produced no data on the use of LF-LAM in children living with HIV. In younger and sicker children, urine sample collection is more cumbersome, as it requires both the child\u2019s and the caregiver\u2019s cooperation, and it may be affected by medical issues, such as dehydration (see Web Annex B.10). Important feasibility challenges are related to the deteriorating quality of the stool sample caused by delays between time of collection and time of processing in the laboratory (see Web Annex B.10). Concurrent testing needs to be framed as a more efficient way of working (i.e. testing two samples concurrently during the same visit, instead of testing one sample during each of two separate visits) that also allows increasing access and reducing costs for patients. According to a laboratory manager, this framing of the benefits outweighing the additional workload, and potentially resulting in reduced work in the long run, will be critical to avoid concurrent testing being perceived as additional work for already overburdened health care workers (see Web Annex B.10). Prior investments made in frontrunner technologies, donor preferences, limited health systems thinking and unnecessary competition between manufacturers all pose challenges to policy adoption and implementation of novel molecular diagnostics. In addition, national in-country health technology and cost-efficacy assessments can delay decisions to implement newer technologies and diagnostic strategies using different samples (see Web Annex B.10). Implementation considerations \u2022 The implementation considerations are the same as those in Sections 2.3.1 and 2.3.2. Monitoring and evaluation \u2022 The monitoring and evaluation considerations are the same as those in Sections 2.3.1 and 2.3.2. Research priorities \u2022 The research priorities are the same as those in Sections 2.3.1 and 2.3.2.", "2. Recommendations for diagnosis of TB disease 71 2.4. Follow-on diagnostic tests for detection of additional drug-resistance after TB confirmation 2.4.1 Low complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents Among 105 countries possessing representative data on resistance to fluoroquinolones from the past 15 years, the proportion of MDR/RR-TB cases with resistance to any fluoroquinolone for which testing was done was 20.1% (95% CI: 15.5\u201325.0%) (1). Thus, rapid and early testing for the detection of fluoroquinolone resistance is essential for determining eligibility for treatment with the all-oral 9\u201312 month standardized shorter regimen for MDR/RR-TB. However, the current limitation with testing for fluoroquinolone resistance is the limited accessibility of current technologies (which are often only available at higher tiers of the health system) and poor yield in paucibacillary specimens. Low complexity automated NAATs are a new class of diagnostics intended for use as a reflex test in specimens determined to be Mtb complex (MTBC)-positive; they offer rapid DST in intermediate and peripheral laboratories. The first product in this class simultaneously detects resistance to isoniazid, fluoroquinolones, ethionamide and amikacin. Results are available in under 90 minutes, leading to faster time to results than the current standard of care, which includes LPAs and culture-based phenotypic DST. An additional value of the tests is the accurate and rapid detection of isoniazid resistance, which is relevant for both RR-TB and rifampicin-susceptible TB; the latter is often undiagnosed and contributes to a large burden of disease. Globally, rifampicin-susceptible TB is estimated to occur in 13.1% (95% CI: 9.9\u201316.9%) of new cases and 17.4% (95% CI: 0.5\u201354.0%) of previously treated cases (1). Thus, this test could also be used as a reflex test to complement existing technologies that only test for rifampicin, allowing the rapid and accurate detection of isoniazid-resistant, rifampicin-susceptible TB. Although these new technologies are excellent at detecting resistance to selected drugs, conventional culture-based phenotypic DST remains important to determine resistance to other anti-TB agents, particularly the new and repurposed medicines such as bedaquiline and linezolid. Recommendations 10. In people with bacteriologically confirmed pulmonary TB, low complexity automated NAATs may be used on sputum for the initial detection of resistance to isoniazid and fluoroquinolones, rather than culture-based phenotypic DST. (Conditional recommendation, moderate certainty of evidence for diagnostic accuracy)", "WHO consolidated guidelines on tuberculosis: Fourth edition 72 11. In people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low complexity automated NAATs may be used on sputum for the initial detection of resistance to ethionamide, rather than DNA sequencing of the inhA promoter. (Conditional recommendation, very low certainty of evidence for diagnostic accuracy) 12. In people with bacteriologically confirmed pulmonary TB and resistance to rifampicin, low complexity automated NAATs may be used on sputum for the initial detection of resistance to amikacin, rather than culture-based phenotypic DST. (Conditional recommendation, low certainty of evidence for diagnostic accuracy) There are several subgroups to be considered for these recommendations: \u2022 The recommendations are based on the evidence of diagnostic accuracy in sputum of adults with bacteriologically confirmed pulmonary TB, with or without rifampicin resistance. \u2022 The recommendations are extrapolated to adolescents and children, based on the generalization of data from adults. \u2022 The recommendations apply to people living with HIV (studies included a varying proportion of such individuals); data stratified by HIV status were not available. \u2022 The recommendations are extrapolated to people with extrapulmonary TB, and testing of non-sputum samples was considered appropriate, which affects the certainty. The panel did not evaluate test accuracy in non-sputum samples directly, including in children; however, extrapolation was considered appropriate given that WHO has recommendations for similar technologies for use on non-sputum samples (e.g. Xpert MTB/RIF and Xpert Ultra). \u2022 Recommendations for detection of resistance to amikacin and ethionamide are only relevant for people who have bacteriologically confirmed pulmonary TB and resistance to rifampicin. Justification and evidence The WHO Global TB Programme initiated an update of the current guidelines and commissioned a systematic review on the use of low complexity automated NAATs for the detection of resistance to isoniazid and second-line TB drugs in people with signs and symptoms of TB. The PICO questions were designed to form the basis for the evidence search, retrieval and analysis: 1. Should low complexity automated NAATs be used on sputum in people with signs and symptoms of pulmonary TB, irrespective of resistance to rifampicin, for detection of resistance to isoniazid, as compared with culture-based phenotypic DST? 2. Should low complexity automated NAATs be used on sputum in people with signs and symptoms of pulmonary TB, irrespective of resistance to rifampicin, for detection of resistance to fluoroquinolones, as compared with culture-based phenotypic DST?", "2. Recommendations for diagnosis of TB disease 73 3. Should low complexity automated NAATs be used on culture isolates in people with signs and symptoms of pulmonary TB, and detected resistance to rifampicin, for detection of resistance to ethionamide, as compared with genotypic sequencing of the inhA promoter? 4. Should low complexity automated NAATs be used on sputum in people with signs and symptoms of pulmonary TB, and detected resistance to rifampicin, for detection of resistance to amikacin, as compared with culture-based phenotypic DST? The databases Ovid Medline (Ovid, 1946 to present) and Embase (Ovid, 1947 to present) were searched for studies evaluating cartridge-based tests using the following search terms: tuberculosis, pulmonary AND Xpert, GeneXpert, Truenat, cartridge, point-of-care systems, drug susceptibility test, isoniazid resistance, fluoroquinolone resistance and second-line injectable drug resistance. Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform were also searched for trials in progress. Searches were run up to 6 September 2020 without language restriction. On 4 November 2020, an additional search was run using the search terms Zeesan and MeltPro. Researchers at FIND, the WHO Global TB Programme, the manufacturer and other experts in the field of TB diagnostics were contacted for information about ongoing and unpublished studies. Data submitted in response to the WHO public call were reviewed. Drug resistance was compared against a phenotypic reference standard (or a genotypic reference standard for ethionamide resistance), as well as a composite reference standard that was constructed by combining the results of phenotypic and genotypic DST results in studies where both had been performed. Data synthesis was structured around the four preset PICO questions, as outlined below. Three web annexes give additional information, as follows: \u2022 details of studies included in the current analysis ( Web Annex A.6: Low complexity automated NAATs); \u2022 a summary of the results and details of the evidence quality assessment (Web Annex A.6: Low complexity automated NAATs); and \u2022 a summary of the GDG panel judgements ( Web Annex A.6: Low complexity automated NAATs). PICO 1: Should low complexity automated NAATs be used on sputum in people with signs and symptoms of pulmonary TB, irrespective of resistance to rifampicin, for detection of resistance to isoniazid, as compared with culture-based phenotypic DST? Three multinational studies with 1605 participants provided data for evaluating isoniazid resistance detection. The reference standard for each of these studies was culture-based phenotypic DST. Each study centre in the multinational", "studies was analysed as a separate study (Fig. 2.4.1.1). Several concerns were expressed about indirectness in the study populations. First, the median prevalence of isoniazid resistance in the included studies was 67.2% (range, 26.8% [Diagnostics for Multidrug Resistant Tuberculosis in Africa \u2013 DIAMA, Benin] to 93.9% [FIND, Moldova]), which is higher than the global estimates for isoniazid resistance. Hence, applicability to settings", "WHO consolidated guidelines on tuberculosis: Fourth edition 74 with a lower prevalence of isoniazid resistance comes with some uncertainty. Second, there are potential differences in the mutations present in isoniazid monoresistant strains and MDR strains; that is, some studies suggest that the mutations found in monoresistant strains are more diverse than the mutations found in MDR strains. Third, although the population for this PICO question is \u201cirrespective of rifampicin resistance\u201d, enrolment criteria in the studies meant that most participants within the included studies had RR-TB. As a result of these concerns, certainty of evidence was downgraded one level for indirectness both for sensitivity and specificity, and the quality (certainty) of evidence was rated moderate both for sensitivity and specificity. Fig. 2.4.1.1 Forest plot of included studies for isoniazid resistance detection, irrespective of rifampicin resistance with culture-based phenotypic DST as the reference standard CI: confidence interval; DIAMA: Diagnostics for Multidrug Resistant Tuberculosis in Africa; DST: drug susceptibility testing; FIND: Foundation for Innovative New Diagnostics; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive. The sensitivity in these three studies ranged from 81% to 100% and the specificity from 87% to 100%. The pooled sensitivity was 94.2% (95% CI: 89.3\u201397.0%) and the pooled specificity was 98.0% (95% CI: 95.2\u201399.2%). PICO 2: Should low complexity automated NAATs be used on sputum in people with signs and symptoms of pulmonary TB, irrespective of resistance to rifampicin, for detection of resistance to fluoroquinolones, as compared with culture-based phenotypic DST? Three multinational studies with 1337 participants provided data for evaluation of detection of fluoroquinolone resistance. The reference standard for each of these studies was culture- based phenotypic DST. Each study centre in the multinational studies was analysed as a separate study (Fig. 2.4.1.2). Specificity estimates were inconsistent, at 84% (FIND, Mumbai), 91% (FIND, New Delhi) and more than 96% for other studies. The heterogeneity in specificity estimates could not be explained. Consequently, the certainty of the evidence was downgraded one level for inconsistency; the quality (certainty) of the evidence was rated high for sensitivity and moderate for specificity.", "2. Recommendations for diagnosis of TB disease 75 Fig. 2.4.1.2 Forest plot of included studies for fluoroquinolone resistance detection, irrespective of rifampicin resistance with culture-based phenotypic DST as the reference standard CI: confidence interval; DIAMA: Diagnostics for Multidrug Resistant Tuberculosis in Africa; DST: drug susceptibility testing; FIND: Foundation for Innovative New Diagnostics; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive. The sensitivity for fluoroquinolone resistance in these three studies ranged from 83% to 100% and the specificity from 84% to 100%. The pooled sensitivity was 93.1% (95% CI: 88.0\u201396.1%) and the pooled specificity was 98.3% (95% CI: 94.5\u201399.5%). PICO 3: Should low complexity automated NAATs be used on culture isolates in people with signs and symptoms of pulmonary TB, and detected resistance to rifampicin, for detection of resistance to ethionamide, as compared with genotypic sequencing of the inhA promoter? One multinational study with 434 participants provided data for evaluating resistance to ethionamide. The reference standard for this study was DNA sequencing of the inhA promoter. Each study centre in the multinational study was analysed as a separate study (Fig. 2.4.1.3). The study was judged to be at very serious risk of bias in the reference standard domain because it did not include all loci (i.e. ethA, ethR and inhA promoter) required for the reference standard to classify the target condition correctly. Against a reference standard of phenotypic DST, the pooled sensitivity was considerably lower, at 51.7% (95% CI: 33.1\u201369.8%). Consequently, certainty of evidence was downgraded two levels for risk of bias for both sensitivity and specificity. In addition, the 95% CIs were wide for both sensitivity and specificity, which could lead to different decisions, depending on which confidence limits are assumed. Consequently, the certainty of the evidence was downgraded one level for imprecision for both sensitivity and specificity; the quality (certainty) of evidence was rated very low for both sensitivity and specificity. Fig. 2.4.1.3 Forest plot of included studies for ethionamide resistance detection with genotypic DST as the reference standard CI: confidence interval; DST: drug susceptibility testing; FIND: Foundation for Innovative New Diagnostics; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive.", "WHO consolidated guidelines on tuberculosis: Fourth edition 76 The sensitivity for ethionamide resistance in this study ranged from 78% to 100% and the specificity from 97% to 100%. The pooled sensitivity was 98.0% (95% CI: 74.2\u201399.9%) and the pooled specificity was 99.7% (95% CI: 83.5\u2013100.0%). PICO 4: Should low complexity automated NAATs be used on sputum in people with signs and symptoms of pulmonary TB, and detected resistance to rifampicin, for detection of resistance to amikacin, as compared with culture-based phenotypic DST? One multinational study with 490 participants provided data for evaluating resistance to amikacin. The reference standard for this study was culture-based phenotypic DST. Each study centre in this multinational study was analysed as a separate study (Fig. 2.4.1.4). The 95% CI for sensitivity was wide, which could lead to different decisions around true positives and false negatives, depending on which confidence limits are assumed. Also, there were few participants with amikacin resistance contributing to this analysis for the observed sensitivity. Consequently, the certainty of the evidence was downgraded two levels for imprecision. Also, there were few participants with amikacin resistance contributing to this analysis for the observed sensitivity. Consequently, the certainty of the evidence was downgraded two levels for imprecision; the quality (certainty) of evidence was rated low for sensitivity and high for specificity. Fig. 2.4.1.4 Forest plot of included studies for amikacin resistance detection with culture-based phenotypic DST as the reference standard CI: confidence interval; DIAMA: Diagnostics for Multidrug Resistant Tuberculosis in Africa; DST: drug susceptibility testing; FIND: Foundation for Innovative New Diagnostics; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive. The sensitivity for amikacin resistance in this study ranged from 75% to 95% and the specificity from 96% to 100%. The pooled sensitivity was 86.1% (95% CI: 75.0\u201392.7%) and the pooled specificity was 98.9% (95% CI: 93.0\u201399.8%). Cost\u2013effectiveness analysis This section answers the following additional question: What is the comparative cost, affordability and cost\u2013effectiveness of implementation of low complexity automated NAATs? A systematic review was conducted, focusing on economic evaluations of low complexity automated NAATs. Four online databases (Embase, Medline, Web of Science and Scopus) were searched for new studies published from 1 January 2010 through 17 September 2020. The citations of all eligible articles, guidelines and reviews were reviewed for additional studies. Experts and test manufacturers were also contacted to identify any additional unpublished studies.", "2. Recommendations for diagnosis of TB disease 77 The objective of the review was to summarize current economic evidence and further understand the costs, cost\u2013effectiveness and affordability of low complexity automated NAATs. Two low complexity automated NAATs were identified: the MeltPro MTB/RIF (Xiamen Zeesan Biotech Co Ltd, China) and the Xpert MTB/XDR assay (Cepheid, Sunnyvale, USA). Only data concerning Xpert MTB/XDR are included in this review. As is the case with Xpert MTB/RIF, the novel XDR assay can be used to test either unprocessed or concentrated sputum. No published studies providing direct evidence on the cost or cost\u2013effectiveness of low complexity automated NAATs were identified. Through direct communication from the Xpert MTB/XDR manufacturer, Cepheid, the low- and middle-income country (LMIC) cost for the XDR cartridge is expected to be US$ 19.80 ex-works. Shipping and customs costs will be additional and will be borne by the ordering nations or organizations, as is currently the case for Xpert MTB/RIF and Ultra cartridges. As with the Xpert MTB/RIF and Ultra assays, the test cartridge costs represent just one component of the total unit test costs that must be considered, with equipment being another important consideration. The Xpert MTB/XDR test will not work on existing six-colour modules and will require laboratories to upgrade to 10-colour GeneXpert modules. There will be different upgrade options for the 10-colour system, with different price points depending on the needs and resources available. Upgrade options include: \u2022 a new 10-colour system \u2013 this is the most costly option, at US$ 9420 for one module to US$ 72 350 for 16 modules, including the GeneXpert platform, computer and scanner; \u2022 a new 10-colour satellite instrument with the GeneXpert connected to an existing system \u2013 this costs from US$ 6495 for one module to US$ 69 525 for 16 modules; and \u2022 converting an existing GeneXpert system from a six-colour to a 10-colour system by replacing modules \u2013 a 10-colour module kit costs US$ 3860. Additional cost considerations for Xpert MTB/XDR include additional testing or repeated testing in the case of indeterminate or non-actionable results (indeterminate, non-determinate or invalid). The potential cost burden of this is likely to vary, depending on the proportion of indeterminate test results across settings and the associated re-testing protocols. No studies that have directly assessed the cost\u2013effectiveness of the Xpert MTB/XDR cartridge were identified. Although extrapolation from other platforms and testing approaches for costing may be", "appropriate, extrapolation of cost\u2013effectiveness data from Xpert MTB/RIF (Ultra) or other NAATs is not advised because of differences in diagnostic accuracy, costs associated with XDR treatment, and the different testing and treatment cascade of care. Several factors are likely to influence the cost\u2013effectiveness of Xpert MTB/XDR; they include diagnostic accuracy, which may lead to more or fewer individuals being diagnosed compared with the standard of care (which in turn will vary, depending on the local standard of care). In addition to diagnostic accuracy associated with the test itself, the diagnostic algorithm and placement of the Xpert MTB/XDR test within the algorithm has important implications. The novel Xpert MTB/XDR provides results in less than 90 minutes. Thus, introduction of this test is likely to result in faster time to a result for genotypic DST and could affect cost\u2013effectiveness by improving the numbers of patients initiating treatment, reducing loss to follow-up and improving survival rates. Costs associated with XDR treatment are likely to be an important driver of cost", "WHO consolidated guidelines on tuberculosis: Fourth edition 78 and cost\u2013effectiveness because previous work has shown that these costs are high compared to diagnostic and other treatment costs. As larger numbers of XDR-positive individuals requiring treatment are identified, total resources required to treat these individuals will increase. In the absence of transmission modelling studies, there is no information on the long-term population level impact of introducing Xpert MTB/XDR. Nevertheless, the benefits of identifying more cases earlier could lead to a reduction in ongoing transmission and potential cost-savings over the long term. This requires thorough investigations through transmission modelling. How large are the resource requirements (costs)? No published studies provided direct evidence about the total resources required. Resource requirements will include the purchase of cartridges (US$ 19.80/cartridge), upgrading of existing platforms to 10-colour modules (an upgrade that will eventually be required for all Xpert platforms: US$ 3860 to >US$ 72 350) and operational and programmatic costs associated with implementing the novel diagnostic. Resource requirements for XDR treatment (e.g. drugs, hospital capacity and staff) are also likely to increase as the number of people diagnosed increases. Total costs will vary, depending on testing volume and prevalence of XDR in the population; also, the impact on the budget will depend on the current standard of care and associated resource use. What is the certainty of the evidence of resource requirements (costs)? Direct costs related to the purchase of cartridges and machinery are provided from the manufacturer; however, several important items related to resource use for implementing Xpert MTB/XDR have not been investigated (e.g. staff time, overhead and operational costs). Differences in resource use between Xpert MTB/XDR and existing approaches will vary across settings using different phenotypic and genotypic DST. There is important variability in costs of staff time and operational costs (e.g. testing volume) across settings. Does the cost\u2013effectiveness of the intervention favour the intervention or the comparison? No cost\u2013effectiveness studies using Xpert MTB/XDR were identified. Extrapolation of cost\u2013 effectiveness data from Xpert MTB/RIF or other NAATs is not advised because of differences in diagnostic accuracy, and costs associated with XDR treatment and the testing and treatment cascade of care. More details on economic evidence synthesis and analysis are provided in Web Annex B.20: Systematic literature review of economic evidence for NAATs to detect TB and DR-TB in adults and children. User perspective This section answers the following question about key informants\u2019 views and", "2. Recommendations for diagnosis of TB disease 79 The synthesis and analysis of qualitative evidence on end-users\u2019 perspectives are discussed above in the section \u201cUser perspective\u201d for moderate complexity automated NAATs: chapter 2.1.2 of the current guidelines. Findings of the review and interviews The main findings of the systematic review and interviews are given below. Where information is from the review, a level of confidence in the QES is given; where it is from interviews, this is indicated with \u2018Interviews\u2019. Is there important uncertainty about or variability in how much end-users value the main outcomes? \u2022 Patients in high burden TB settings value: \u2013 getting an accurate diagnosis and reaching diagnostic closure (finally knowing \u201cwhat is wrong with me\u201d); \u2013 avoiding diagnostic delays because they exacerbate existing financial hardships and emotional and physical suffering, and make patients feel guilty for infecting others (especially children); \u2013 having accessible facilities; and \u2013 reducing diagnosis-associated costs (e.g. travel, missing work) as important outcomes of the diagnostic. QES: moderate confidence \u2022 Low complexity automated NAATs, when compared with existing tests or sputum microscopy, are appreciated by health care professionals because of: \u2013 the rapidity and accuracy of the results; \u2013 the confidence that a result generates to start treatment and motivate patients; \u2013 the diversity of sample types; \u2013 the ability to detect drug resistance earlier or at all, for as many drugs as possible (altering a clinician\u2019s risk perception of drug resistance in children), and the consequence of avoiding costlier investigations or hospital stays. QES: high confidence \u2013 Compared with other available diagnostic methods, the cartridge has a quicker turnaround time for first- and second-line DST. Health care professionals value the faster turnaround time, the potential ability to reflex samples from the Xpert MTB/RIF to the Xpert MTB/XDR cartridge, and receiving information on multiple drugs and high-level or low-level resistance simultaneously, because it could enable quicker diagnosis and optimized treatment for patients. Interviews \u2022 Laboratory technicians appreciate low complexity automated NAATs for the following reasons: \u2013 Overall, the tests improve laboratory work compared with sputum microscopy in terms of ease of use, ergonomics and biosafety. QES: high confidence \u2013 These tests require minimal user steps, and the GeneXpert platform is a familiar system that people feel comfortable running and interpreting. Interviews", "WHO consolidated guidelines on tuberculosis: Fourth edition 80 \u2022 Laboratory managers appreciate that monitoring of laboratory work and training is easier than with sputum microscopy, and that use of low complexity automated NAATs eases staff retention because it increases staff satisfaction and is symbolic of progress within the TB world. QES: low confidence What would be the impact on health equity? The impact on health equity would be similar to that of moderate complexity automated NAATs: Chapter 2.1.2 of the current guidelines. Is the intervention acceptable to key stakeholders? The acceptability to key stakeholders is similar to that of moderate complexity automated NAATs: Chapter 2.1.2 of the current guidelines. The identified challenges in implementing the use of low complexity automated NAATs and accumulated delays at every step may compromise the added value and benefits identified by the users (e.g. avoiding delays, keeping costs low, accurate results, information on drug resistance and easing laboratory work), ultimately leading to use. QES: high confidence If these values are not met, it can be assumed that users are less likely to find low complexity automated NAATs acceptable. Is the intervention feasible to implement? \u2022 Low complexity automated NAATs may decrease the workload in the laboratory in terms of freeing up time for laboratory staff. However, based on experience with Xpert MTB/ RIF (Ultra), the introduction of a new class of technologies may increase the workload of laboratory staff if added onto existing work without adjusting staffing arrangements or if the new technology does not replace existing diagnostic tests. QES: moderate confidence \u2022 Low complexity automated NAATs require less user training than other DST methods (e.g. LPA and culture), making these tests more feasible to implement than methods with more user steps and those that require significant additional training. Interview study Implementation of new diagnostics must be accompanied by training for clinicians, to help them interpret results from new molecular tests and understand how this relates to the treatment of a patient. In the past, with the introduction of Xpert MTB/RIF (Ultra), this has been a challenge and has led to underuse. QES: high confidence and interview study Introduction of Xpert MTB/RIF (Ultra) has also led to overreliance on results of cartridge- based NAATs at the expense of clinical acumen. QES: moderate confidence \u2022 Introduction of new diagnostics must also be accompanied by guidelines and algorithms that support clinicians and laboratories in communicating with each", "2. Recommendations for diagnosis of TB disease 81 \u2022 An efficient sample transportation system, with sustainable funding mechanisms, is crucial for feasibility, especially if an algorithm requires multiple samples at different times from different collection points, as is the case when dealing with DR-TB. If mishandled during preparation, there is a risk that the sample may become contaminated and yield inconclusive results on molecular diagnostics. Participants cited good personnel skills, standardized operating procedures and significant laboratory infrastructure as essential in reducing sample contamination in their laboratory. Interviews \u2022 The feasibility of low complexity automated NAATs is challenged if there is an accumulation of diagnostic delays or underuse (or both) at every step in the process, mainly because of health system factors: \u2013 non-adherence to testing algorithms, testing for TB or MDR-TB late in the process, empirical treatment, false negatives due to technology failure, large sample volumes and staff shortages, poor or delayed sample transport and sample quality, poor or delayed communication of results, delays in scheduling follow-up visits and recalling patients, and inconsistent recording of results; \u2013 lack of sufficient resources and maintenance (e.g. stock-outs; unreliable logistics; lack of funding, electricity, space, air conditioners and sputum containers; dusty environment; and delayed or absent local repair option); \u2013 inefficient or unclear workflows and patient flows (e.g. inefficient organizational processes, poor links between providers, and unclear follow-up mechanisms or information on where patients need to go); and \u2013 lack of data-driven and inclusive national implementation processes. QES: high confidence \u2022 The feasibility of using low complexity automated NAATs is also challenged by the value of diagnosing MTB over DR-TB at primary care. This situation makes the NAAT less feasible as a baseline test, although it would fit at a district or intermediate level laboratory. Implementation considerations Factors to consider when implementing low complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents are as follows: \u2022 local epidemiological data on resistance prevalence should guide local testing algorithms, whereas pretest probability is important for the clinical interpretation of test results; \u2022 the cost of a test varies depending on parameters such as the number of samples in a batch and the staff time required; therefore, a local costing exercise should be performed; \u2022 low, moderate and high complexity tests have successive increase in technical competency needs (qualifications and skills) and staff time, which affects planning and budgeting; \u2022 availability and", "timeliness of local support services and maintenance should be considered when selecting a provider; \u2022 laboratory accreditation and compliance with a robust quality management system (including appropriate quality control) are essential for sustained service excellence and trust; \u2022 training of both laboratory and clinical staff will ensure effective delivery of services and clinical impact; \u2022 use of connectivity solutions for communication of results is encouraged, to improve efficiency of service delivery and time to treatment initiation;", "WHO consolidated guidelines on tuberculosis: Fourth edition 82 \u2022 rapid and early testing for the detection of fluoroquinolone resistance is essential before starting treatment with the all-oral MDR/RR-TB shorter regimen (i.e. 6\u20139 months); this may also become relevant (depending on the epidemiological context) if new shorter drug- susceptible TB regimens that include fluoroquinolones are introduced; \u2022 these tests can be used to rule in ethionamide resistance, but not to rule out resistance, because mutations conferring resistance to ethionamide are not limited to the inhA promoter region \u2013 they also include ethA, ethR and other genes; \u2022 culture-based phenotypic DST may still be required, particularly among those with a high pretest probability of resistance when the low complexity automated NAATs does not detect drug resistance; in addition, culture-based phenotypic DST: \u2013 remains important to determine resistance to other anti-TB agents, particularly the new and repurposed medicines, and to monitor the emergence of additional drug resistance; \u2013 does not apply to ethionamide because it is unreliable and poorly reproducible; \u2022 for second-line injectable drugs, the panel evaluated the performance in detecting resistance to amikacin only because both kanamycin and capreomycin are no longer recommended for the treatment of DR-TB; and \u2022 culture-based phenotypic DST may be important to confirm amikacin susceptibility in situations where it is appropriate to use this medicine, to balance risk and benefit. Research priorities Research priorities for low complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents are as follows: \u2022 diagnostic accuracy, in specific patient populations (e.g. children, people living with HIV, and patients with signs and symptoms of extrapulmonary TB) and in non-sputum samples; \u2022 impact of diagnostic technologies on clinical decision-making and outcomes that are important to patients (e.g. cure, mortality, time to diagnosis and time to start treatment) in all patient populations; \u2022 impact of specific mutations on treatment outcomes among people with DR-TB; \u2022 use, integration and optimization of diagnostic technologies in the overall landscape of testing and care, as well as diagnostic pathways and algorithms; \u2022 economic studies evaluating the costs, cost\u2013effectiveness and cost\u2013benefit of different diagnostic technologies; \u2022 qualitative studies evaluating equity, acceptability, feasibility and end-user values of different diagnostic technologies; \u2022 effect of non-actionable results (indeterminate, non-determinate or invalid) on diagnostic accuracy and outcomes that are important to patients; \u2022 evaluation of low complexity automated NAATs for initial TB detection, in addition to its use as", "a follow-on test, in all people with signs and symptoms of TB, in children and in people living with HIV; and \u2022 the potential utility of katG resistance detection to identify MDR-TB clones that may be missed because they do not have an RRDR mutation (e.g. the Eswatini MDR-TB clone, which has both the katG S315T and the non-RRDR rpoB I491F mutation).", "2. Recommendations for diagnosis of TB disease 83 2.4.2 First-line LPAs In 2008, WHO approved the use of commercial LPAs for detecting MTBC in combination with resistance to rifampicin and isoniazid in sputum smear-positive specimens (direct testing) and in cultured isolates of MTBC (indirect testing). A systematic review at that time evaluated the diagnostic accuracy of two commercially available LPAs \u2013 the INNO-LiPA Rif.TB assay (Innogenetics, Ghent, Belgium), and the GenoType\u00ae MTBDRplus (version 1), hereafter referred to as Hain version 1 \u2013 and provided evidence for WHO\u2019s endorsement (37, 38). Excellent accuracy was reported for both tests in detecting rifampicin resistance, but their diagnostic accuracy for isoniazid resistance had lower sensitivity, despite the high specificity. Because there were inadequate data to allow stratification by smear status, WHO\u2019s recommendation for using LPAs was limited to culture isolates or smear-positive sputum specimens. Further data have since been published on the use of LPAs; newer versions of LPA technology have now been developed, such as the Hain GenoType MTBDR plus version 2, hereafter referred to as Hain version 2; and other manufacturers have entered the market, including Nipro (Tokyo, Japan), which developed the Genoscholar\u2122 NTM+MDRTB II, hereafter referred to as Nipro. In 2015, FIND evaluated the Nipro and the Hain version 2 LPAs, and compared them with Hain version 1. The study demonstrated equivalence among the three commercially available LPAs for detecting TB and resistance to rifampicin and isoniazid (5). Table 2.4.2.1 Class criteria for LPAs Purpose Detection of resistance to first- and/ or second-line TB drugs Principle of action DNA-based reverse hybridization, or line probe, assays Complexity Reagents Reagents are available within standardized kits and may have temperature requirements for storage. Skills Advanced technical skills (i.e., multiple sample or reagent handling steps, precision pipetting, molecular workflows may be required) Pipetting Multiple precision pipetting steps required by the procedure. Testing Procedure May require multiple specimen treatment steps before transferring the specimen into a sealed container for multi-step testing. Manual or automated DNA extraction Manual or automated real-time PCR Instrument-based reverse hybridization Type of test result reporting Manual Setting of use Molecular laboratory (special infrastructure and separate of spaces for different parts of the testing procedure are required)", "WHO consolidated guidelines on tuberculosis: Fourth edition 84 Recommendation 13. For persons with a sputum smear-positive specimen or a cultured isolate of MTBC, commercial molecular LPAs may be used as the initial test instead of phenotypic culture-based DST to detect resistance to rifampicin and isoniazid. (Conditional recommendation, moderate certainty in the evidence for the test\u2019s accuracy) Remarks 1. These recommendations apply to the use of LPAs for testing sputum smear-positive specimens (direct testing) and cultured isolates of MTBC (indirect testing) from both pulmonary and extrapulmonary sites. 2. LPAs are not recommended for the direct testing of sputum smear-negative specimens. 3. These recommendations apply to the detection of MTBC and the diagnosis of MDR-TB, but acknowledge that the accuracy of detecting resistance to rifampicin and isoniazid differs and, hence, that the accuracy of a diagnosis of MDR-TB is reduced overall. 4. These recommendations do not eliminate the need for conventional culture-based DST, which will be necessary to determine resistance to other anti-TB agents and to monitor the emergence of additional drug resistance. 5. Conventional culture-based DST for isoniazid may still be used to evaluate patients when the LPA result does not detect isoniazid resistance. This is particularly important for populations with a high pretest probability of resistance to isoniazid. 6. These recommendations apply to the use of LPA in children based on the generalization of data from adults. Test description LPAs are a family of DNA strip-based tests that can detect the MTBC strain and determine its drug resistance profile through the pattern of binding of amplicons (DNA amplification products) to probes targeting the following: specific parts of the MTBC genome (for MTBC detection), the most common resistance-associated mutations to first-line and second-line agents, or the corresponding wild-type DNA sequence (for detection of resistance to anti-TB drugs) (38). LPAs are based on reverse hybridization DNA strip technology and involve three steps: DNA extraction from M. tuberculosis culture isolates or directly from patient specimens, followed by multiplex PCR amplification and then reverse hybridization with visualization of amplicon binding (or lack thereof) to wild-type and mutation probes (8). Although LPAs are more technically complex to perform than the Xpert MTB/RIF assay, they can detect isoniazid resistance. Testing platforms have been designed for a reference laboratory setting and are thus most applicable to high TB burden countries. Results can be obtained in 5 hours.", "2. Recommendations for diagnosis of TB disease 85 Some of these steps can be automated, making the method quicker and more robust, and reducing the risk of contamination. The Hain version 1 and version 2 assays include rpoB probes to detect rifampicin resistance, katG probes to detect mutations associated with high-level isoniazid resistance, and inhA promoter probes to detect mutations usually associated with low-level isoniazid resistance. The probes used to detect wild-type and specific mutations are the same for both versions of the Hain LPA. Similarly, the Nipro assay allows for the identification of MTBC, and resistance to rifampicin and isoniazid. The Nipro assay also differentiates M. avium, M. intracellulare and M. kansasii from other non-tuberculous mycobacteria. The rpoB, katG and inhA promoter mutation probes are the same for the three assays, with the exception of the katG S315N mutation, which is included in the Nipro assay but not in Hain version 1 or version 2. There are some minor variations in the codon regions covered for the wild type among Hain version 1 and version 2, and the Nipro. Justification and evidence In 2015, WHO commissioned an updated systematic review of the accuracy of commercial LPAs for detecting MTBC, and resistance to rifampicin and isoniazid. A total of 74 studies were identified, comprising 94 unique datasets (see Web Annex A.7: \u201cFL-LPA\u201d). Of these 94 datasets, 83 evaluated Hain version 1, five evaluated Hain version 2, and six evaluated the Nipro assay. Only one of the studies performed head-to-head testing of all three target LPAs on directly tested clinical specimens and indirectly tested isolates, and these data were included as six separate datasets (9). No studies performed LPA testing on specimens and culture isolates from the same patients, precluding direct within-study comparisons. Following the 2015 systematic review, the WHO Global TB Programme convened a GDG in March 2016 to assess the data and update the 2008 policy recommendations on using commercial LPAs to detect MTBC, and resistance to isoniazid and rifampicin. The PICO questions are given in Box 2.4.2.1. LPAs were compared with a phenotypic culture-based DST reference standard, and a composite reference standard that combined the results from genetic sequencing with results from phenotypic culture-based DST. Phenotypic DST was the primary reference standard applied to all participants for all analyses. These analyses were stratified \u2013 first, by susceptibility or resistance to rifampicin or isoniazid (or both) and second, by", "WHO consolidated guidelines on tuberculosis: Fourth edition 86 1. Should LPAs be used to guide clinical decisions to use rifampicin in the direct testing of specimens and the indirect testing of culture isolates from patients with signs and symptoms consistent with TB? 2. Should LPAs be used to guide clinical decisions to use isoniazid in the direct testing of specimens and the indirect testing of culture isolates from patients with signs and symptoms consistent with TB? 3. Should LPAs be used to diagnose MDR-TB in patients with signs and symptoms consistent with TB? 4. Should LPAs be used to diagnose TB in patients with signs and symptoms consistent with TB but for whom sputum-smear results are negative? Box 2.4.2.1 PICO questions Several studies contributed to either sensitivity (no true positives and no false negatives) or specificity (no true negatives and no false positives) but not to both. For these studies, a univariate, random-effects meta-analysis of the estimates of sensitivity or specificity was performed separately, to make optimal use of the data. The results from the univariate analysis (using all studies) were compared with the results from the bivariate analysis of the subset of studies that contributed to estimates of both sensitivity and specificity. If there were at least four studies for index tests with data that contributed only to sensitivity or specificity, a univariate, random-effects meta-analysis was performed to assess one summary estimate, assuming no correlation between sensitivity and specificity. In cases in which there were fewer than four studies, or where substantial heterogeneity was evident on forest plots that precluded a meta-analysis, a descriptive analysis was performed for these index tests. Forest plots were visually assessed for heterogeneity among the studies within each index test and in the summary plots, for variability in estimates and the width of the prediction region (a wider prediction region suggests more heterogeneity). Implementation considerations Adopting LPAs to detect rifampicin and isoniazid resistance does not eliminate the need for conventional culture and DST capacity. Culture and phenotypic culture-based DST have critical roles in monitoring patients\u2019 responses to treatment and detecting additional resistance to second-line agents. \u2022 The adoption of LPA should be phased in, starting at national or central reference laboratories, or those with proven capability to conduct molecular testing. Expansion could be considered, within the context of a country\u2019s plans for laboratory strengthening, the availability of suitable personnel in peripheral centres and the", "quality of specimen transport systems. \u2022 Adequate and appropriate laboratory infrastructure and equipment should be provided, to ensure that the required precautions for biosafety and the prevention of contamination are met \u2013 specimen processing for culture and procedures for manipulating cultures must be performed in biological safety cabinets in TB-containment laboratories.", "2. Recommendations for diagnosis of TB disease 87 \u2022 Laboratory facilities for LPAs require at least three separate rooms, one each for DNA extraction, pre-amplification procedures, and amplification and post-amplification procedures. To avoid contamination, access to molecular facilities must be restricted, a unidirectional workflow must be implemented and stringent cleaning protocols must be established. \u2022 Appropriate laboratory staff should be trained to conduct LPA procedures. Staff should be supervised by a senior staff member with adequate training and experience in molecular assays. A programme for the external quality assessment of laboratories using LPAs should be developed as a priority. \u2022 Mechanisms for rapidly reporting LPA results to clinicians must be established, to provide patients with the benefit of early diagnosis. The same infrastructure used for performing LPAs can be used also to perform second-line LPAs. \u2022 LPAs are designed to detect TB and resistance to rifampicin and isoniazid in the direct testing of processed sputum samples, and in the indirect testing of culture isolates of MTBC. The use of LPAs with other respiratory samples (e.g. from BAL or gastric aspiration) or extrapulmonary samples (e.g. tissue samples, CSF or other body fluids) have not been adequately evaluated. \u2022 The availability of second-line agents is critical in the event that resistance to rifampicin or isoniazid, or both, is detected. \u2022 For patients with confirmed MDR/RR-TB, second-line LPAs are recommended to detect additional resistance to second-line anti-TB agents. Research priorities \u2022 Development of improved understanding of the correlation between the detection of resistance-conferring mutations using culture-based DST and patient outcomes. \u2022 Review of evidence to confirm or revise different critical concentrations used in culture- based DST methods. \u2022 Determination of the limit of detection for LPA in detecting heteroresistance. \u2022 Determination of needs for training, assessing competency and ensuring quality assurance. \u2022 Gathering of more evidence on the impact on mortality of initiating appropriate treatment for MDR-TB. \u2022 Meeting the STARD for future diagnostic studies. \u2022 Performance of country-specific cost\u2013effectiveness and cost\u2013benefit analyses of LPA use in different programmatic settings. 2.4.3 Second-line LPAs Genotypic (molecular) methods have considerable advantages for scaling up programmatic management and surveillance of DR-TB, offering rapid diagnosis, standardized testing, potential for high throughput and fewer requirements for laboratory biosafety. Molecular tests for detecting drug resistance \u2013 for example, the GenoType MTBDRsl assay (Hain Lifescience, Nehren, Germany), hereafter referred to as MTBDR sl (10) \u2013 have shown promise for the", "WHO consolidated guidelines on tuberculosis: Fourth edition 88 MTBDRsl (version 1.0) was the first commercial SL-LPA for detection of resistance to second- line TB drugs. In 2015, the manufacturer developed and made commercially available version 2.0 of the MTBDRsl assay. Version 2.0 detects the mutations associated with fluoroquinolones and second-line injectable drug (SLID) resistance detected by version 1.0, and additional mutations. Once a diagnosis of MDR/RR-TB has been established, an SL-LPA can be used to detect additional resistance to second-line drugs. The MTBDRsl assay incorporates probes to detect mutations within genes that are associated with resistance to either fluoroquinolones or SLIDs ( gyrA and rrs for version 1.0 and those genes plus gyrB and the eis promoter for version 2.0). The presence of mutations in these regions does not necessarily imply resistance to all the drugs within a particular class. Although specific mutations within these regions may be associated with different levels of resistance (i.e. different minimum inhibitory concentrations) to each drug within these classes, the extent of cross-resistance is not completely understood. Recommendations 14. For patients with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to fluoroquinolones. (conditional recommendation, moderate certainty in the evidence for test accuracy) 15. For patients with confirmed MDR/RR-TB, SL-LPA may be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to the SLIDs. (conditional recommendation, low certainty in the evidence for test accuracy) Remarks \u2022 These recommendations apply to the use of SL-LPA for testing sputum specimens (direct testing) and cultured isolates of M. tuberculosis (indirect testing) from both pulmonary and extrapulmonary sites. Direct testing on sputum specimens allows for the earlier initiation of appropriate treatment. \u2022 These recommendations apply to the direct testing of sputum specimens from MDR/RR-TB, irrespective of the smear status, while acknowledging that the indeterminate rate is higher when testing smear-negative sputum specimens than with smear-positive sputum specimens. \u2022 These recommendations do not eliminate the need for conventional phenotypic DST capacity, which will be necessary to confirm resistance to other drugs and to monitor the emergence of additional drug resistance. \u2022 Conventional phenotypic DST can still be used in the evaluation of patients with negative SL-LPA results, particularly in populations with a high pretest probability for resistance to fluoroquinolones or SLID (or both). \u2022 These recommendations apply to the use of SL-LPA in children with confirmed", "2. Recommendations for diagnosis of TB disease 89 \u2022 Resistance-conferring mutations detected by SL-LPA are highly correlated with phenotypic resistance to SLID. \u2022 Given the high specificity for detecting resistance to fluoroquinolones and SLID, the positive results of SL-LPA could be used to guide the implementation of appropriate infection control precautions. Test description The SL-LPA is based on the same principle as the first-line LPA. The assay procedure can be performed directly using a processed sputum sample or indirectly using DNA isolated and amplified from a culture of M. tuberculosis. Direct testing involves the following steps: 1. Decontamination (e.g. with sodium hydroxide) and concentration of a sputum specimen by centrifugation. 2. Isolation and amplification of DNA. 3. Detection of the amplification products by reverse hybridization. 4. Visualization using a streptavidin-conjugated alkaline phosphatase colour reaction. Indirect testing includes only Steps 2\u20134. The observed bands, each corresponding to a wild- type or resistance-genotype probe, can be used to determine the drug susceptibility profile of the analysed specimen. The assay can be performed and completed within a single working day. Further details on the test process and practical support for implementation can be found in the WHO operational handbook. Module 3: diagnosis. The index test used was MTBDRsl versions 1.0 and 2.0. These SL-LPAs detect specific mutations associated with resistance to the class of fluoroquinolones (including ofloxacin, levofloxacin, moxifloxacin and gatifloxacin) and SLIDs (including kanamycin, amikacin and capreomycin) in the MTBC. The MTBDRsl LPA detects mutations in the gyrA quinolone resistance-determining region (codons 85\u201397) and rrs (codons 1401, 1402 and 1484), and version 2.0 of the test added detection of mutations in the gyrB quinolone resistance-determining region (codons 536\u2013541) and the eis promoter region (codons \u201310 to \u201314) (40). Version 2.0 is therefore expected to have improved sensitivity for resistance detection to these classes of drugs. Lastly, while version 1.0 included detection of mutations in embB that may encode for resistance to ethambutol, it was omitted from version 2.0 due to its status as a first line anti-TB drug. Therefore, this review did not determine the accuracy for ethambutol resistance. More data are needed to better understand the correlation of the presence of certain fluoroquinolone resistance-conferring mutations with phenotypic DST resistance and with patient outcomes. Justification and evidence In March 2016, the WHO Global TB Programme convened a GDG to assess available data on the use of the MTBDRsl assay. WHO commissioned a", "WHO consolidated guidelines on tuberculosis: Fourth edition 90 The PICO questions in Box 2.4.3.1 were designed to form the basis for the evidence search, retrieval and analysis. 1. Should the MTBDRsl test be used to guide clinical decisions to use fluoroquinolones in patients with confirmed MDR/RR-TB? \u00ce Direct testing (stratified by smear grade: smear negative; scanty; 1+; \u22652+). \u00ce Indirect testing. 2. Should the MTBDRsl test be used to guide clinical decisions to use SLIDs in patients diagnosed with MDR/RR-TB? \u00ce Direct testing (stratified by smear grade: smear negative; scanty; 1+; \u22652+). \u00ce Indirect testing. Box 2.4.3.1 PICO questions Twenty-nine unique studies were identified; of these, 26 evaluated the MTBDR sl version 1.0 assay (including 21 studies from the original Cochrane review). Three studies (one published and two unpublished) evaluated version 2.0. Data for version 1.0 and version 2.0 of the MTBDRsl assay were analysed separately. A phenotypic culture-based DST reference standard was used for the primary analyses. These analyses were stratified first by susceptibility or resistance to a particular drug, and second by type of SL-LPA testing (indirect testing or direct testing). Performance of SL-LPA on sputum specimens and culture isolates In patients with MDR/RR-TB, a positive SL-LPA result for fluoroquinolone resistance (as a class) or SLID resistance (as a group) can be treated with confidence. The diagnostic accuracy of SL-LPA is similar when performed directly on sputum specimens or indirectly on cultured isolates of M. tuberculosis. Given the confidence in a positive result and the ability of the test to provide rapid results, the GDG felt that SL-LPA may be considered for use as an initial test for resistance to the fluoroquinolones and when relevant SLIDs. However, when the test shows a negative result, phenotypic culture-based DST may be necessary, especially in settings with a high pretest probability for resistance to either fluoroquinolones or SLIDs (or both). The use of SL-LPA in routine care should improve the time to the diagnosis of fluoroquinolone and where relevant SLIDs, especially when used for the direct testing of sputum specimens of patients with confirmed MDR/RR-TB. Early detection of drug resistance should allow for the earlier initiation of appropriate patient therapy and improved patient health outcomes. Overall, the test performs well in the direct testing of sputum specimens from patients with confirmed MDR/RR-TB, although the indeterminate rate is higher when testing smear-negative sputum specimens compared with smear-positive sputum specimens. When the MTBDRsl", "2. Recommendations for diagnosis of TB disease 91 (less with version 2.0, although very limited data) and hence require repeat or additional testing. However, if the same test were to be applied to the testing of smear-negative sputum specimens from patients without confirmed TB or DR-TB (i.e. patients suspected of having DR-TB), the indeterminate rate for the test would be significantly higher. Given the test\u2019s sensitivity and specificity when an SL-LPA is done directly on sputum, the GDG felt that SL-LPAs can be used for the testing of all sputum specimens from patients with confirmed MDR/RR-TB, irrespective of whether the microscopy result is positive or negative. For the reasons mentioned above (inadequate data owing to too few studies on version 2.0), results are not presented here for version 2.0. For MTBDR sl version 2.0, the data were either too sparse or too heterogeneous to combine in a meta-analysis or to compare indirect and direct testing. Three studies evaluated the MTBDRsl version 2.0 in 562 individuals, including 111 confirmed cases of TB with fluoroquinolone resistance by indirect testing on a culture of M. tuberculosis compared with a phenotypic culture-based DST reference standard. Estimates of sensitivity ranged from 84% to 100% and specificity from 99% to 100%. See Web Annex B.15: Drug concentrations used in culture-based DST SL-LPA for details of the drug concentrations used in culture-based DST to evaluate the performance of SL-LPAs in each included study. Implementation considerations The SL-LPA should only be used to test specimens from patients with confirmed MDR/RR-TB. Adoption of SL-LPAs does not eliminate the need for conventional culture and DST capability. Despite good specificity of SL-LPAs for the detection of resistance to fluoroquinolones and the SLIDs, culture and phenotypic DST is required to completely exclude resistance to these drug classes as well as to other second-line drugs. The following implementation considerations apply: \u2022 SL-LPAs cannot determine resistance to individual drugs in the class of fluoroquinolones. Resistance-conferring mutations detected by SL-LPAs are highly correlated with phenotypic resistance to ofloxacin and levofloxacin. \u2022 Mutations in some regions (e.g. the eis promoter region) may be responsible for causing resistance to one drug in a class more than other drugs within that class. For example, the eis C14T mutation is associated with kanamycin resistance in strains from Eastern Europe. \u2022 SL-LPAs should be used in the direct testing of sputum specimens, irrespective of whether samples are smear negative or", "smear positive. \u2022 SL-LPAs are designed to detect TB and resistance to fluroquinolones and SLIDs from sputum samples. Other respiratory samples (e.g. BAL and gastric aspirates) or extrapulmonary samples (tissue samples, CSF or other body fluids) have not been adequately evaluated. \u2022 Culture and phenotypic DST plays a critical role in the monitoring of a patient\u2019s response to treatment, and in detecting additional resistance to second-line drugs during treatment. \u2022 SL-LPAs are suitable for use at the central or national reference laboratory level; they can also be used at the regional level if the appropriate infrastructure can be ensured (three separate rooms are required). \u2022 All patients identified by SL-LPAs should have access to appropriate treatment and ancillary medications.", "WHO consolidated guidelines on tuberculosis: Fourth edition 92 Research priorities \u2022 Development of improved understanding of the correlation between the detection of resistance-conferring mutations with phenotypic DST results and with patient outcomes. \u2022 Development of improved knowledge of the presence of specific mutations detected with SL-LPA correlated with minimum inhibitory concentrations for individual drugs within the classes of fluoroquinolones and SLIDs. \u2022 Determination of the limit of detection of SL-LPA for the detection of heteroresistance. \u2022 Gathering of more evidence on the impact of MTBDRsl on appropriate MDR-TB treatment initiation and mortality. \u2022 Strongly encourage that future studies follow the recommendations in the STARD (11) statement to improve the quality of reporting. \u2022 Performance of country-specific cost\u2013effectiveness and cost\u2013benefit analyses of the use of SL-LPA in different programmatic settings. 2.4.4 High complexity reverse hybridization-based NAATs for detection of pyrazinamide resistance Pyrazinamide is an important antibiotic for the treatment of both drug-susceptible TB and DR-TB because of its unique ability to eradicate persisting bacilli and its synergistic properties with other antibiotics. Mono-resistance to pyrazinamide is rare; however, pyrazinamide resistance is strongly associated with MDR/RR-TB, with an estimated 30\u201360% of MDR/RR-TB also resistant to pyrazinamide. Thus, for people diagnosed with RR-TB, it is important to detect the presence of pyrazinamide resistance so that clinicians can make an informed decision on whether to include or exclude pyrazinamide in the treatment regimen. The high complexity hybridization- based NAAT may be used for diagnosis of pyrazinamide resistance on patient isolates; however, performance of this test requires appropriate infrastructure and skilled staff. Recommendation 16. In people with bacteriologically confirmed TB, high complexity reverse hybridization-based NAATs may be used on Mtb culture isolates for detection of pyrazinamide resistance rather than culture-based phenotypic DST. (Conditional recommendation, very low certainty of evidence for diagnostic accuracy) In terms of subgroups to be considered for this recommendation, no special considerations are required (e.g. for children, people living with HIV and those with extrapulmonary TB), given that the test is recommended for use on culture isolates. Test description Nipro (Osaka, Japan) developed Genoscholar\u2122 PZA-TB, an LPA with reverse hybridization- based technology for detection of pyrazinamide resistance (12). This assay is a commercially available rapid molecular test for detection of pyrazinamide resistance. Compared with MTBDRplus and MTBDRsl LPA, the Genoscholar PZA-TB LPA does not include specific mutant", "2. Recommendations for diagnosis of TB disease 93 probes because resistance mutations are widespread across the entire pncA gene with no predominant mutations. Instead, the Genoscholar PZA-TB assay targets a 700 base pair (bp) fragment covering the entire pncA gene and promoter region up to nucleotide \u201318 of the wild- type H37Rv reference strain. Fig. 2.4.4.1 Nipro GenoScholar PZA-TB II strip (a) and Nipro GenoScholar PZA-TB II kit contents (b) DNA extracted from cultures is amplified with primers by PCR. Amplified DNA is then hybridized to complementary oligonucleotide probes that are bound on a membrane strip. Streptavidin labelled with alkaline phosphatase is then added, to bind to any hybrids formed in the previous step. Next, a substrate is added, and an enzymatic reaction results in purple bands, which are visually interpreted. The absence of wild-type probe binding indicates the presence of a mutation. The first version of the assay contained 47 probes, which covered the pncA promoter and open reading frame. The second version contained 48 probes, three of which ( pncA 16, 17 and 35) represent silent mutations known to be genetic markers not associated with pyrazinamide resistance: Gly60Gly (probe 16), Ser65Ser (probe 17) and Thr142Thr (probe 35). Justification and evidence The Genoscholar PZA-TB LPA assay, which is already commercially available, could potentially be implemented for diagnosis of pyrazinamide resistance in routine care. However, limited data have been published on the diagnostic accuracy of the assay. This systematic review with meta-analysis aimed to assist in collating all the available data to understand the diagnostic accuracy of the pyrazinamide LPA assay for detection of pyrazinamide resistance in TB patients, to guide policy-makers and clinicians. a b", "WHO consolidated guidelines on tuberculosis: Fourth edition 94 The WHO Global TB Programme initiated an update of the current guidelines and commissioned a systematic review on the use of high complexity reverse hybridization-based NAATs for detection of pyrazinamide resistance in people with signs and symptoms of TB. Two PICO questions were designed to form the basis for the evidence search, retrieval and analysis: 1. Should high complexity reverse hybridization-based NAATs on sputum be used to diagnose pyrazinamide resistance in patients with microbiologically confirmed pulmonary TB, irrespective of resistance to rifampicin, as compared with culture-based phenotypic DST or composite reference standard? 2. Should high complexity reverse hybridization-based NAATs on isolates be used to diagnose pyrazinamide resistance in patients with microbiologically confirmed pulmonary TB, irrespective of resistance to rifampicin, as compared with culture-based phenotypic DST? The databases searched were PubMed, Web of Science and Embase, and they were searched without language or date restrictions. The search query was (PZA OR pyrazinamide OR pncA) AND (tuberculosis) AND (\u201cline-probe assay\u201d OR LPA OR \u201chybridization-based technology\u201d). In addition, we approached Nipro (Osaka, Japan) to identify non-published data. The microbiological reference standard was defined either as phenotypic culture-based DST performed using BD MGIT 960 PZA liquid assay or another acceptable phenotypic assay, or as genotypic DST performed using either targeted sequencing of the pncA gene or whole genome sequencing. In the case of genotypic DST, all samples with a pncA wild type were defined as being susceptible, while any variant in pncA was considered resistant, which implicitly would categorize \u201csilent\u201d mutations as resistant. In contrast, the composite reference standard was defined by classifying all samples with pncA wild type, pncA silent mutations and neutral mutations as being susceptible, while any other variant in pncA was considered resistant (13). Data synthesis was structured around the two preset PICO questions, as outlined below. Three web annexes give additional information, as follows: \u2022 details of studies included in the current analysis (Web Annex A.9: High complexity reverse hybridization-based NAATs); \u2022 a summary of the results and details of the evidence quality assessment (Web Annex A.9: High complexity reverse hybridization-based NAATs); and \u2022 a summary of the GDG panel judgements ( Web Annex A.9: High complexity reverse hybridization-based NAATs). PICO 1: Should high complexity reverse hybridization-based NAATs on sputum be used to diagnose pyrazinamide resistance in patients with microbiologically confirmed pulmonary TB, irrespective of resistance to rifampicin, as compared with", "2. Recommendations for diagnosis of TB disease 95 standard. The number of studies and participants were considered insufficient to make a conclusion on a diagnostic accuracy of high complexity reverse hybridization-based NAATs on sputum. PICO 2: Should high complexity reverse hybridization-based NAATs on isolates be used to diagnose pyrazinamide resistance in patients with microbiologically confirmed pulmonary TB, irrespective of resistance to rifampicin, as compared with culture-based phenotypic DST? Seven studies with a total of 964 participants provided data for evaluation of these NAATs for detection of pyrazinamide resistance compared with a phenotypic culture-based reference standard (Fig. 2.4.4.2). The studies suffered from selection bias because they selected isolates with a wide range of different pncA mutations rather than a representative sample from a population. Thus, the evidence was downgraded by one level for risk of bias. The included studies did not directly address the review question; hence, the evidence was downgraded one level for indirectness. The Burhan trial and the Rienthong study are outliers for their sensitivities compared with the other studies; hence, the evidence was downgraded one level for inconsistency. Taking these judgements together, the quality (certainty) of evidence was rated very low for sensitivity and low for specificity. Fig. 2.4.4.2 Forest plot of included studies for pyrazinamide resistance detection, irrespective of rifampicin resistance with culture-based phenotypic DST as the reference standard CI: confidence interval; DST: drug susceptibility testing; FN: false negative; FP: false positive; TB: tuberculosis; TN: true negative; TP: true positive. The overall sensitivity for pyrazinamide resistance in these seven studies ranged from 36% to 100% and the specificity from 96% to 100%. The pooled sensitivity was 81.2% (95% CI: 75.4\u201385.8%) and specificity was 97.8% (95% CI: 96.5\u201398.6%). More details on diagnostic accuracy of the high complexity reverse hybridization-based NAATs, including comparison with genotypic and composite reference standards are available in Web Annex 4.17: High complexity reverse hybridization-based NAATs: diagnostic accuracy for detection of resistance to pyrazinamide. A systematic review.", "WHO consolidated guidelines on tuberculosis: Fourth edition 96 Cost\u2013effectiveness analysis This section answers the following additional question: What is the comparative cost, affordability and cost\u2013effectiveness of implementation of high complexity reverse hybridization-based NAATs? A systematic review was carried out, focusing on economic evaluations of high complexity reverse hybridization-based NAATs. Four online databases (Embase, Medline, Web of Science and Scopus) were searched for new studies published from 1 January 2010 through 17 September 2020. The citations of all eligible articles, guidelines and reviews were reviewed for additional studies. The experts and test manufacturers were also contacted to identify any additional unpublished studies. The objective of the review was to summarize current economic evidence and further understand the costs, cost\u2013effectiveness and affordability of high complexity reverse hybridization- based NAATs. No published studies were identified assessing costs or cost\u2013effectiveness using the commercially available high complexity hybridization-based NAAT (Genoscholar PZA-TB II, Nipro Japan). Indirect evidence was available from several sources. Four studies examining other commercially available LPAs (Genotype MTBDRsl and MTBDRplus, Hain Lifescience) were identified. The Genoscholar PZA LPA was developed for use with the Nipro automated MultiBlot; however, a recent unpublished trial12 demonstrated that the Twincubator by Hain Lifescience could be used successfully with this LPA. This finding could make it easier to implement the Genoscholar PZA LPA in selected settings where Hain Lifescience equipment is already in use. How large are the resource requirements (costs)? No direct evidence from published studies was found regarding the total resources required. Resource requirements will include the purchase of test kits (Genoscholar PZA LPA: US$ 16/ test kit consumables only), and the equipment, which is available for US$ 14 000. Operational costs are frequently several times greater than test kit costs (and will vary across settings), but are not accounted for usually. Nipro hopes that further reductions in test costs can be achieved when the Genoscholar PZA-TB II product is distributed globally. Unit test costs for the Genotype MTBDRsl and MTBDRplus ranged from US$ 23.46 to US$ 108.70 (14\u201315), with higher unit test costs in countries such as China and South Africa, largely driven by higher staff wages and operational costs. Extrapolations from unit test costs using different LPAs should be done with caution, and they are not intended to be directly transferrable estimates. Nevertheless, these indirect data do suggest that the total unit test cost of the Genoscholar PZA-TB II is likely several-fold higher than", "the unit test kit consumable cost of US$ 16. Total costs will vary, depending on testing volume, numbers eligible for testing and prevalence of pyrazinamide resistance in the population. The impact on the budget will depend on the current standard of care, diagnostic and care pathways, and associated resource use. 12 Leen Rigouts: Validation study of Genoscholar PZA LPA in three Supranational TB Reference Laboratories.", "2. Recommendations for diagnosis of TB disease 97 What is the certainty of the evidence of resource requirements (costs)? Direct costs related to test kits and machinery are available, whereas several important items related to resource use (e.g. staff time, and overhead and operational costs associated with implementing Genoscholar PZA-TB II) have not been investigated. Differences in resource use between Genoscholar PZA-TB II and existing approaches will vary across settings that are using different phenotypic and genotypic DST. Also, there is important variability in costs of staff time and operation (e.g. testing volume) across settings. Does the cost\u2013effectiveness of the intervention favour the intervention or the comparison? No cost\u2013effectiveness studies were identified using the Genoscholar PZA-TB II. Extrapolation of cost\u2013effectiveness data from other LPAs is not advised owing to differences in diagnostic accuracy, resistance prevalence, and the testing and treatment cascade of care. More details on economic evidence synthesis and analysis are given in Web Annex 4.9: Systematic literature review of economic evidence for NAATs to detect TB and DR-TB in adults and children. User perspective This section answers the following questions about key informants\u2019 views and perspectives on the use of high complexity reverse hybridization-based NAATs: \u2022 Is there important uncertainty about or variability in how much end-users value the main outcomes? \u2022 What would be the impact on health equity? \u2022 Is the intervention acceptable to key stakeholders? \u2022 Is the intervention feasible to implement? Findings of the review and interviews The main findings of the systematic review and interviews are given below. Where information is from the review, a level of confidence in the QES is given; where it is from interviews, this is indicated with \u2018Interviews\u2019. Is there important uncertainty about or variability in how much end-users value the main outcomes? \u2022 Patients in high burden TB settings value: \u2013 getting an accurate diagnosis and reaching diagnostic closure (finally knowing \u201cwhat is wrong with me\u201d); \u2013 avoiding diagnostic delays because they exacerbate existing financial hardships and emotional and physical suffering, and make patients feel guilty for infecting others (especially children); \u2013 having accessible facilities; and \u2013 reducing diagnosis-associated costs (e.g. travel, missing work) as important outcomes of the diagnostic. QES: moderate confidence", "WHO consolidated guidelines on tuberculosis: Fourth edition 98 \u2022 The high complexity reverse hybridization-based NAATs meet some preferences and values of laboratory staff and clinicians, in that the current test: \u2013 provides quicker results about pyrazinamide resistance than other available methods (e.g. culture DST); \u2013 can provide information on different concentration levels; and \u2013 targets a drug that is widely used in first-line TB treatment. Interviews What would be the impact on health equity? The impact on health equity would be similar to that of moderate complexity automated NAATs (Section 2.1.2), plus the following: \u2022 Lengthy diagnostic delays, underuse of diagnostics, lack of TB diagnostic facilities at lower levels and too many eligibility restrictions hamper access to prompt and accurate testing and treatment, particularly for vulnerable groups. QES: high confidence Applicability to three index tests also confirmed in interviews \u2022 Staff and managers voiced concerns about the sustainability of funding and maintenance, complex conflicts of interest between donors and implementers, and the strategic and equitable use of resources, which makes it difficult to ensure equitable access to cartridge-based diagnostics. QES: high confidence \u2022 For patients, access to clear, comprehensible and dependable information on what TB diagnostics are available to them and how to interpret results is a vital component of equity; lack of such access represents an important barrier for patients. Interviews \u2022 New treatment options need to be matched with new diagnostics: it is important to improve access to treatment based on new diagnostics, and to improve access to diagnostics for new treatment options. Interviews \u2022 The speed at which WHO guidelines are changing does not match the speed at which many country programmes are able to implement the guidelines. This translates into differential access to new TB diagnostics and treatment: \u2013 between countries (i.e. between those that can and cannot quickly keep up with the rapidly changing TB diagnostic environment); and \u2013 within countries (i.e. between patients who can and cannot afford the private health system that is better equipped to quickly adopt new diagnostics and policies). Interviews Is the intervention acceptable to key stakeholders? \u2022 Acceptability of a high complexity reverse hybridization-based NAAT depends on how well the test performs on different samples, because laboratory staff question how well LPA methods work on smear-negative samples. If samples need to be cultured before the pyrazinamide LPA is run, this may undermine the benefits of this method\u2019s quicker turnaround", "2. Recommendations for diagnosis of TB disease 99 laboratory staff may require further clarification and justification in some settings as to why this specific drug test is being prioritized, given that it is not currently part of routine DST. \u2022 Specific feasibility challenges (training and infrastructure requirements, sample quality result interpretation system), general feasibility challenges (as identified in the interview study and QES, respectively) and accumulated delays risk undoing the added value and benefits identified by the users (e.g. avoiding delays and drug-resistance information). QES high confidence and interviews Is the intervention feasible to implement? \u2022 The feasibility of implementing the pyrazinamide LPA is challenged by the significant training and laboratory infrastructure required to implement this method. Feasibility also hinges on the availability of an automated interpretation system, because the result is difficult to interpret. Interviews Implementation considerations Factors to consider when implementing a high complexity hybridization-based NAAT for detection of pyrazinamide resistance are as follows: \u2022 There are specific concerns about the complexity and difficulty of interpretation. The large number of bands makes it difficult to read the result of the high complexity reverse hybridization-based NAAT. \u2022 Local epidemiological data on resistance prevalence should guide local testing algorithms, whereas pretest probability is important for the clinical interpretation of test results. \u2022 The cost of a test varies, depending on the number of samples in a batch, staff time and other parameters requiring a local costing exercise to be performed. \u2022 Low, moderate, and high complexity tests have a successive increase in technical competency needs (qualifications and skills) and staff time, impacting planning and budgeting. \u2022 Availability and timeliness of local support service and maintenance should be considered when selecting a provider. \u2022 Laboratory accreditation and compliance with a robust quality management system (including appropriate quality control) is essential for sustained service excellence and trust. \u2022 Training of both laboratory and clinical staff will ensure effective delivery of services and clinical impact. \u2022 Use of connectivity solutions for communication of results is encouraged, to improve efficiency of service delivery and time to treatment initiation. \u2022 Based on a multinational, population-based study, levels of pyrazinamide resistance varied widely in the surveyed settings (3.0\u201342.1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance (49). \u2022 Implementation of a high complexity hybridization-based NAAT requires laboratories with the required infrastructure, space and functional sample referral systems. \u2022 Because there are several manual", "WHO consolidated guidelines on tuberculosis: Fourth edition 100 Research priorities Research priorities for a high complexity hybridization-based NAAT for detection of pyrazinamide resistance are as follows: \u2022 diagnostic accuracy of high complexity hybridization-based NAATs indirect testing on sputum and non-sputum samples in people with signs and symptoms of TB, with or without resistance to rifampicin; \u2022 impact of diagnostic technologies on clinical decision-making and outcomes important to patients (e.g. cure, mortality, time to diagnosis and time to start treatment) in all patient populations; \u2022 impact of specific mutations on treatment outcomes among people with DR-TB; \u2022 use, integration and optimization of diagnostic technologies in the overall landscape of testing and care, as well as diagnostic pathways and algorithms; \u2022 economic studies evaluating the costs, cost\u2013effectiveness and cost\u2013benefit of diagnostic technologies; \u2022 qualitative studies evaluating equity, acceptability, feasibility and end-user values of diagnostic technologies; and \u2022 interpretation of the results from a high complexity hybridization-based NAAT compared with sequencing and newer evidence on genotypic and phenotypic associations. 2.4.5 Targeted next-generation sequencing Targeted NGS technology couples amplification of selected genes with NGS technology to detect resistance to many drugs with a single test. Also, since targeted NGS can interrogate entire genes to identify specific mutations associated with resistance, tests based on this technology may be more accurate than existing WRDs. In addition, new tests based on NGS can detect resistance to new and repurposed drugs that are not currently included in any other molecular assays. Hence, tests based on targeted NGS offer great potential to provide comprehensive resistance detection matched to modern treatment regimens. Recommendations 17. In people with bacteriologically confirmed pulmonary TB disease, targeted next-generation sequencing technologies may be used on respiratory samples to diagnose resistance to rifampicin, isoniazid, fluoroquinolones, pyrazinamide and ethambutol rather than culture-based phenotypic drug susceptibility testing. (Conditional recommendation, certainty of evidence moderate [isoniazid and pyrazinamide],low [rifampicin, fluoroquinolones and ethambutol]) Remarks \u2022 Priority should be assigned to those at higher risk of resistance to first-line treatment medications, including individuals who: \u2013 continue to be smear or culture positive after 2 or more months of treatment, or experience treatment failure; \u2013 have previously had TB treatment,", "2. Recommendations for diagnosis of TB disease 101 \u2013 are in contact with a person known to have resistance to TB drugs; or \u2013 reside in settings or belong to subgroups where there is a high probability of resistance to either rifampicin, isoniazid or fluoroquinolone (used in new shorter regimens), or where there is a high prevalence of M. tuberculosis strains harbouring mutations not detected by other rapid molecular tests. \u2022 This recommendation is conditional because of the lack of data on health benefits, the variable certainty of evidence on diagnostic accuracy, and the fact that accuracy is suboptimal for certain drugs. In addition, because this is a new technology that has not yet been widely implemented, there is still limited and variable evidence on costs, cost\u2013effectiveness and feasibility of implementation. 18. In people with bacteriologically confirmed rifampicin-resistant pulmonary TB disease, targeted NGS technologies may be used on respiratory samples to diagnose resistance to isoniazid, fluoroquinolones, bedaquiline, linezolid, clofazimine, pyrazinamide, ethambutol, amikacin and streptomycin rather than culture-based phenotypic drug susceptibility testing. (Conditional recommendation, certainty of evidence high [isoniazid, fluoroquinolones and pyrazinamide], moderate [ethambutol], low [bedaquiline, linezolid, clofazimine and streptomycin], very low [amikacin]) Remarks \u2022 Priority should be given to those at a higher risk of resistance to medications used for the treatment of RR-TB, including individuals who: \u2013 continue to be smear or culture positive after 2 months or more of treatment or have experienced treatment failure; \u2013 have previously had TB treatment, including with the new and repurposed drugs; \u2013 are in contact with a person known to have resistance to TB drugs, including the new and repurposed drugs; or \u2013 have pre-XDR-TB with resistance to fluoroquinolones. \u2022 As above, this recommendation is conditional because of the lack of data on health benefits, the variable certainty of evidence on diagnostic accuracy, the fact that accuracy is suboptimal for certain drugs, and limited and variable evidence on costs, cost\u2013effectiveness and feasibility of implementation.", "WHO consolidated guidelines on tuberculosis: Fourth edition 102 The products and drugs for which eligible data met the class-based performance criteria are listed below: Deeplex\u00ae Myc-TB (Genoscreen, France): rifampicin, isoniazid, pyrazinamide, ethambutol, fluoroquinolones, bedaquiline, linezolid, clofazimine, amikacin and streptomycin AmPORE-TB\u00ae (Oxford Nanopore Diagnostics, United Kingdom): rifampicin, isoniazid, fluoroquinolones, linezolid, amikacin and streptomycin TBseq\u00ae (Hangzhou ShengTing Medical Technology Co., China): ethambutol Where a product has not yet met the requirements for a specific drug (i.e., the drug is not listed), further improvements to the product are needed, and a review of the evidence is necessary before clinical use. Box 2.4.5.1 Test description Three products met the inclusion criteria for detection of drug resistance to at least one of the anti-TB drugs under evaluation. \u2022 The Deeplex\u00ae Myc-TB test (Genoscreen, France) is a targeted NGS-based kit for the simultaneous identification of mycobacterial species, genotyping and prediction of drug resistance of MTBC strains, directly applicable on sputum samples (50). The assay relies on deep sequencing of a 24-plex amplicon mix, and it targets 18 MTBC gene regions associated with resistance to anti-TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, fluoroquinolones, amikacin, kanamycin, capreomycin, streptomycin, ethionamide, bedaquiline, clofazimine and linezolid). Mycobacterial species identification is performed by targeting the hsp65 gene; the spoligotyping target (CRISPR/Direct Repeat locus) and phylogenetic single nucleotide polymorphisms (SNPs) in targets associated with drug resistance are used for MTBC strain genotyping. The assay is performed using the Nextera XT and DNA Flex library preparation kits on the iSeq 100, MiniSeq, MiSeq and NextSeq sequencing platforms (Illumina). The solution includes an automated analysis pipeline of the sequencing data in a secure online application with integrated databases for results interpretation. \u2022 The AmPORE-TB\u00ae test (Oxford Nanopore Diagnostics, United Kingdom) \u2013 previously referred to as Nano-TB) \u2013 is a targeted NGS-based kit for the simultaneous identification of mycobacterial species and the detection of MTBC genetic variants associated with antimicrobial resistance in DNA extracted from sputum samples. 13 The assay relies on sequencing of a 27-plex amplicon mix: 24 drug-resistance targets, a genotyping target, a non-tuberculous mycobacteria (NTM) identification target (hsp65) and an internal control. The 24 drug-resistance targets are MTBC gene regions that are associated with resistance to various TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, fluoroquinolones, 13 Oxford Nanopore Diagnostics provided a draft protocol for the test.", "2. Recommendations for diagnosis of TB disease 103 amikacin, kanamycin, capreomycin, streptomycin, ethionamide, bedaquiline, clofazimine, linezolid and delamanid). Mycobacterial species identification is performed by targeting the hsp65 gene; the spoligotyping target (CRISPR/Direct Repeat locus) is used for MTBC strain genotyping. The assay is performed using the OND AmPORE-TB kit (OND-TBDR001-XX) and Flow Cells (OND-FLO-MIN001-XX) on the GridION Diagnostic Sequencing System (OND). The sequencing control software on the device can automatically start and report the results for the analysis workflows installed. The AmPORE-TB includes analysis software pre-installed on a device that processes readouts produced by the sequencing control software and creates an easy-to-interpret report, all performed locally on the device. \u2022 The TBseq\u00ae test (Hangzhou ShengTing Medical Technology Co., China) is a kit based on targeted NGS that is used for the simultaneous identification of mycobacterial species and the prediction of drug resistance of MTBC strains; it is directly applicable to clinical specimens such as sputum and BAL fluid (51). The assay relies on deep sequencing of a multiplex amplification mix and it targets 21 MTBC genes associated with resistance to TB drugs (rifampicin, isoniazid, pyrazinamide, ethambutol, fluoroquinolones, amikacin, kanamycin, capreomycin, streptomycin, para-aminosalicylic acid, cycloserine, ethionamide or prothionamide, bedaquiline, clofazimine and linezolid). Mycobacterial species identification is performed by targeting the 16S and hsp65 gene regions. The assay is performed using the Universal Gene Sequencing Kit (ShengTing) to generate libraries that are sequenced on either a MinION or a GridION platform (Oxford Nanopore Technologies). The solution includes automated analysis software (Nano TNGS V1.0) for sequencing data processing and a secure online application (TBseq\u00ae Web App) with integrated databases for interpretation of results. Justification and evidence Diagnostic accuracy and health benefits Two health questions were designed using the PICO approach, to form the basis for the evidence search, retrieval and analysis. 1. Should targeted NGS as the initial test be used to diagnose drug resistance in individuals with bacteriologically confirmed pulmonary TB disease? This question applies to: \u2013 rifampicin, using a composite reference standard of phenotypic DST and whole genome sequencing (WGS), and Xpert MTB/RIF\u00ae or Xpert Ultra\u00ae; \u2013 isoniazid, using phenotypic DST as the reference standard; \u2013 levofloxacin, using phenotypic DST as the reference standard; \u2013 moxifloxacin, using phenotypic DST as the reference standard; \u2013 pyrazinamide, using a composite reference standard of phenotypic DST and WGS; and \u2013 ethambutol, using a composite reference standard of phenotypic DST and WGS. 2. Should targeted", "WHO consolidated guidelines on tuberculosis: Fourth edition 104 \u2013 moxifloxacin, using phenotypic DST as the reference standard; \u2013 pyrazinamide, using a composite reference standard of phenotypic DST and WGS; \u2013 bedaquiline, using phenotypic DST as the reference standard; \u2013 linezolid, using phenotypic DST as the reference standard; \u2013 clofazimine, using phenotypic DST as the reference standard; \u2013 amikacin, using phenotypic DST as the reference standard; \u2013 ethambutol, using a composite reference standard of phenotypic DST and WGS; and \u2013 streptomycin, using phenotypic DST as the reference standard. A broad search was conducted to find, appraise and synthesize evidence about health benefits and the diagnostic test accuracy of targeted NGS compared with phenotypic drug sensitivity testing for patients with bacteriologically confirmed TB or with bacteriologically confirmed rifampicin-resistant pulmonary TB disease. A comprehensive search of three databases (Medline, Ovid Embase and Scopus) for relevant citations was performed. No date restriction was applied and the search was initially performed on 7 September 2022 and repeated on 17 January 2023. In addition, WHO made a public call for data and contacted well-known experts in the field to ask whether they had, or knew of, unpublished data that could contribute. No data were found for the impact of targeted NGS on patient-level health effects. For the analysis of diagnostic accuracy, because few data were available in the literature, all data identified from the literature were included after correspondence with the authors. Hence, no manual data extraction from publications was required. A post-hoc decision was made to perform only an individual patient data (IPD) meta-analysis; thus, any study that could not provide IPD was excluded. Two report authors made independent assessments of methodological quality using QUADAS-2. Disagreements were resolved by discussion and uncertainties or disagreements were reviewed by an independent third party. Subanalyses were performed to assess the diagnostic test accuracy in PLHIV and for semiquantitative results (derived from cycle thresholds) from Xpert MTB/RIF \u00ae or Xpert Ultra\u00ae, where \u201cvery low\u201d or \u201clow\u201d concentrations of M. tuberculosis were compared with \u201cmedium\u201d or \u201chigh\u201d concentrations. The very low or low semiquantitative categories represent paucibacillary disease states, such as those frequently observed in paediatric TB. Data were included from both published and unpublished prospective, observational clinical studies of targeted NGS platform diagnostic accuracy. All studies where targeted NGS had been performed directly from processed clinical samples were included, whereas those performed exclusively on cultured isolates were excluded. All", "studies were required to have comparator phenotypic DST data as a reference; in the cases of rifampicin, ethambutol and pyrazinamide, studies were required to also have WGS, to allow a composite reference to be generated. Rifampicin resistance results and semiquantitative results from Xpert MTB/RIF\u00ae or Xpert Ultra\u00ae were requested from all studies. Given that this was a review of the diagnostic accuracy of a class of diagnostic platforms, all the data from each platform alone were analysed to assess which to include in an analysis to inform a class recommendation. Where the performance of any one platform appeared to be an outlier for sensitivity or specificity, that platform was excluded from subsequent meta- analyses. A platform was considered to be an outlier for a particular drug if the point estimate", "2. Recommendations for diagnosis of TB disease 105 for sensitivity was more than 10 percentage points worse than the best performing platform, or where the point estimate for specificity was more than 5 percentage points worse. An IPD meta-analysis was performed instead of a classical meta-analysis, because the studies identified in the literature were generally too small to contribute to a classical meta-analysis, particularly for the new and repurposed drugs. In addition, this type of approach allowed for relevant co-variables to be included in the model; it could also control for repeated testing on the same samples using different platforms, which was the case for much of the available data. For each dependent variable, a multivariable model included a number of co-variables as fixed effects. These included rifampicin resistance as determined by Xpert MTB/RIF\u00ae or Xpert Ultra\u00ae for all drugs other than rifampicin; semiquantitative cycle threshold (CT) value from Xpert MTB/ RIF\u00ae or Xpert Ultra\u00ae; and a co-variable to indicate which samples featured in duplicate, meaning that some samples were sequenced on two different platforms and thus were represented twice in the analysis. For models looking specifically at diagnostic test accuracy in PLHIV, the HIV test result was included as a co-variable. Finally, the study site was included as a random effect. The models were run in Stata (version 17) using the melogit command, and the outputs were transformed using the margins command. Models were run for all PICO questions for sensitivity and specificity. The certainty of the evidence of the pooled studies was assessed systematically for each of the PICO questions using the GRADE approach, which produces an overall quality assessment (or certainty) of evidence and has a framework for translating evidence into recommendations. The GRADEpro Guideline Development Tool software (16) was used to generate summary of findings tables for the sensitivity and specificity of each drug. The numbers of samples classified as true, false positive or negative were then calculated across a range of three prevalences of drug resistance, chosen to be representative of different global settings. The quality of evidence was rated as high (not downgraded), moderate (downgraded one level), low (downgraded two levels) or very low (downgraded more than two levels), based on five factors: risk of bias, indirectness, inconsistency, imprecision and other considerations. The quality (certainty) of evidence was downgraded by one level when a serious issue was identified and by two levels when a", "very serious issue was identified in any of the factors used to judge the quality of evidence. The data sources for the IPD data analysis are shown in Fig. 2.4.5.1. The analysis included data from published studies, a large multicountry trial conducted by FIND, and several other studies across multiple countries. Most of the studies only evaluated the Deeplex assay, while the FIND trial evaluated both the Deeplex and the AmPORE-TB. Only one study evaluated TBseq. For each drug, one or two platforms were dropped from the analysis based on the overall number of resistant or susceptible samples available for that platform and drug, or because the accuracy of the platform did not meet the diagnostic test accuracy criteria for inclusion when compared with the best performing platform.", "WHO consolidated guidelines on tuberculosis: Fourth edition 106 Fig. 2.4.5.1 Studies included in the IPD meta-analysis for targeted NGS ERJ: European Respiratory Journal; FIND: Foundation for Innovative New Diagnostics; IPD: individual patient data; NGS: next-generation sequencing; NICD: National Institute for Communicable Diseases; UTLD: International Union Against Tuberculosis and Lung Diseases. Data synthesis was structured around the two preset PICO questions, as outlined below. PICO 1: Should targeted NGS as the initial test be used to diagnose drug resistance in patients with bacteriologically confirmed pulmonary TB disease? The available evidence included in the final pooled analysis varied by drug, from 12 studies with 1440 participants for the sensitivity of isoniazid to three studies with 269 participants for the specificity of pyrazinamide (Table 2.4.5.1). The pooled estimates were determined using a multivariable, mixed-effects model. All drugs were downgraded by one level for indirectness for sensitivity and specificity, because all studies were enriched for rifampicin resistance, leading to applicability concerns. In addition, for rifampicin, levofloxacin and pyrazinamide, specificity was downgraded a further level for imprecision; however, for ethambutol, it was downgraded for risk of bias because different samples were used for the index and reference tests. The overall certainty of the evidence for test accuracy ranged from moderate to very low. The test performance was determined to be accurate for all drugs included in the assessment, with a pooled sensitivity of at least 95% for isoniazid, moxifloxacin and ethambutol, more than 93% for rifampicin and levofloxacin, and 88% for pyrazinamide. The pooled specificity was at least 96% for all drugs. The reference standard was culture-based phenotypic DST for isoniazid, levofloxacin and moxifloxacin, and a combination of phenotypic DST and WGS for rifampicin, pyrazinamide and ethambutol. The percentage of tests with indeterminate results ranged from 9% (levofloxacin and moxifloxacin) to 18% (pyrazinamide), with higher indeterminate rates in samples with lower bacterial load (semiquantitative category low or very low). 0 200 400 600 800 Number of samples SRSI_EritreaSRSI_Italy Diama_Ethiopia Diama_MaliDiama_Benin Frontiers2021_FranceTuberculosis2021_India ERJ2021_SNRLIJTLD2022_India icddr ,b_Bangladesh NICD_South Africa Diama_Cameroon Diama_GuineaDiama_RwandaFIND_South Africa FIND_GeorgiaTBSeq_ChinaFIND_India From the literature: \u2022 ERJ 2021 (SNRL Germany) \u2022 Frontiers 2021 (France) \u2022 Tuberculosis 2021 (India) \u2022 IJTLD 2022 (India) Unpublished: \u2022 FIND \u2022 Georgia \u2022 India \u2022 South Africa \u2022 Diama \u2022 Benin \u2022 Guinea \u2022 Cameroon \u2022 Rwanda \u2022 Mali \u2022 Ethiopia \u2022 NICD, South Africa \u2022 icddr,b (Bangladesh) \u2022 San Raffaele Scientific Institute, Italy \u2022 Italy \u2022 Eritrea \u2022 TBSeq, China Platforms:", "2. Recommendations for diagnosis of TB disease 107 Table 2.4.5.1 The accuracy and certainty of evidence of targeted NGS for the detection of resistance to anti-TB drugs among bacteriologically confirmed pulmonary TB Drug Reference standard Accuracy % (95% CI) Studies (persons) Certainty in evidence Rifampicin Phenotypic DST+WGS Se: 93.1 (87.0\u201399.2) 9 (1436) Moderate Phenotypic DST+WGS Sp: 96.2 (88.6\u2013100) 7 (271) Low Isoniazid Phenotypic DST Se: 95.8 (92.8\u201398.7) 12 (1440) Moderate Phenotypic DST Sp: 97.0 (95.1\u201398.9) 12 (517) Moderate Levofloxacin Phenotypic DST Se: 94.2 (88.4\u201399.9) 6 (654) Low Phenotypic DST Sp: 96.2 (93.4\u201398.9) 7 (913) Moderate Moxifloxacin Phenotypic DST Se: 95.6 (92.4\u201398.7) 6 (652) Moderate Phenotypic DST Sp: 96.3 (93.2\u201399.5) 8 (921) Moderate Pyrazinamide Phenotypic DST+WGS Se: 88.4 (85.2\u201391.7) 3 (346) Moderate Phenotypic DST+WGS Sp: 98.5 (97.1\u2013100) 3 (269) Moderate Ethambutol Phenotypic DST+WGS Se: 95.8 (94.0\u201397.6) 4 (432) Low Phenotypic DST+WGS Sp: 99.3 (98.2\u2013100) 4 (268) Low CI: confidence interval; DST: drug susceptibility testing; NGS: next-generation sequencing; Se: sensitivity; Sp: specificity; TB: tuberculosis; WGS: whole genome sequencing. There were no data on the impact of targeted NGS on patient outcomes such as time to treatment or treatment outcome. PICO 2: Should targeted NGS be used to diagnose drug resistance in patients with bacteriologically confirmed rifampicin-resistant pulmonary TB disease? The available evidence varied by drug, from 12 studies with 1440 participants for sensitivity of isoniazid to three studies with 31 participants for sensitivity of bedaquiline (Table 2.4.5.2). The pooled estimates were determined using a multivariable, mixed-effects model. The overall certainty was high for some of the drugs. Levofloxacin was downgraded one level for inconsistency. Bedaquiline and linezolid were downgraded by two levels for imprecision in sensitivity because the number of resistant samples was below the threshold set and the confidence intervals were wide. Clofazimine was also downgraded by two levels, one for inconsistency (because two studies were outliers) and another level for imprecision (because the confidence intervals were wide). Amikacin was downgraded by one level for sensitivity and specificity because critical concentrations outside those recommended by WHO were used for a large proportion of samples. Amikacin sensitivity was further downgraded by two more levels, one for inconsistency and the other for imprecision. Ethambutol was downgraded by one level for risk of bias because different samples were used for the index and reference tests. Streptomycin specificity was downgraded by two levels, one for inconsistency and the other for imprecision. The overall certainty of", "WHO consolidated guidelines on tuberculosis: Fourth edition 108 The test performance among people with RR-TB was determined to be accurate for isoniazid, levofloxacin, moxifloxacin, ethambutol and streptomycin (pooled sensitivity \u226595%) and acceptable for pyrazinamide (90%), bedaquiline (68%), linezolid (69%), clofazimine (70%) and amikacin (87%). The pooled specificity was 95% or greater for all drugs except streptomycin (75%). The reference standard was culture-based phenotypic DST for all drugs except for ethambutol and pyrazinamide, where a combination of phenotypic DST and WGS was used. The percentage of tests with indeterminate results ranged from 9% (levofloxacin and moxifloxacin) to 21% (ethambutol); indeterminate rates were higher in samples with a lower bacterial load (semiquantitative category low or very low). Table 2.4.5.2 The accuracy and certainty of evidence of targeted NGS for the detection of resistance to anti-TB drugs among bacteriologically confirmed rifampicin-resistant pulmonary TB Drug Reference standard Accuracy % (95% CI) Studies (persons) Certainty in evidence Isoniazid Phenotypic DST Se: 96.5 (93.8\u201399.2) 12 (1440) High Phenotypic DST Sp: 95.8 (91.8\u201399.8) 12 (517) High Levofloxacin Phenotypic DST Se: 95.8 (90.4\u2013100) 6 (654) Moderate Phenotypic DST Sp: 96.0 (93.1\u201398.9) 7 (913) High Moxifloxacin Phenotypic DST Se: 96.5 (93.6\u201399.5) 6 (652) High Phenotypic DST Sp: 95.2 (91.0\u201399.4) 8 (921) High Pyrazinamide Phenotypic DST+WGS Se: 90.0 (86.8\u201393.2) 3 (346) High Phenotypic DST+WGS Sp: 98.6 (96.8\u2013100) 3 (269) High Bedaquiline Phenotypic DST Se: 67.9 (42.6\u201393.2) 3 (31) Low Phenotypic DST Sp: 97.0 (94.3\u201399.7) 4 (519) High Linezolid Phenotypic DST Se: 68.9 (38.7\u201399.1) 4 (31) Low Phenotypic DST Sp: 99.8 (99.6\u2013100) 6 (1093) High Clofazimine Phenotypic DST Se: 70.4 (34.6\u2013100) 4 (36) Low Phenotypic DST Sp: 96.3 (93.2\u201399.3) 6 (789) High Amikacin Phenotypic DST Se: 87.4 (74.5\u2013100) 5 (115) Very low Phenotypic DST Sp: 99.0 (98.4\u201399.6) 8 (1003) Moderate Ethambutol Phenotypic DST+WGS Se: 96.7 (95.0\u201398.4) 4 (431) Moderate Phenotypic DST+WGS Sp: 98.4 (96.1\u2013100) 4 (123) Moderate Streptomycin Phenotypic DST Se: 98.1 (96.1\u2013100) 5 (493) High Phenotypic DST Sp: 75.0 (59.5\u201390.5) 5 (250) Low CI: confidence interval; DST: drug susceptibility testing; NGS: next-generation sequencing; Se: sensitivity; Sp: specificity; TB: tuberculosis; WGS: whole genome sequencing.", "2. Recommendations for diagnosis of TB disease 109 There were no data on the impact of targeted NGS on patient outcomes such as time to treatment or treatment outcome. Three web annexes give additional information, as follows: \u2022 details of studies included in the current analysis (Web Annex A.10: Review of the diagnostic accuracy of targeted NGS technologies for detection of drug resistance among people diagnosed with TB); \u2022 a summary of the results and details of the evidence quality assessment (Web Annex A.10: GRADE profiles of targeted next-generation sequencing for detection of TB drug resistance); and \u2022 a summary of the GDG panel judgements ( Web Annex A.10: Evidence to decision tables: targeted next-generation sequencing for detection of TB drug resistance). Cost\u2013effectiveness analysis The cost and cost\u2013effectiveness data for targeted NGS were assessed through a systematic review of the published literature and a generalized model-based cost\u2013effectiveness analysis commissioned by WHO. The systematic review on the cost and cost\u2013effectiveness of using either targeted NGS or WGS to diagnose DR-TB searched three databases: PubMed, Embase and Scopus. The search was run on 30 October 2022 and had no time restriction. All costing data were inflated to 2021 US dollars. Findings were synthesized descriptively, given the considerable degree of heterogeneity in study methodology and outcomes. Among the studies included in the systematic review, three were on targeted NGS only, three were on targeted NGS and WGS, and four were on WGS only. For targeted NGS based on a single study (n=1), the cost per sample was between US$ 69.64 for Illumina MiSeq on 24 samples, and US$ 73.47 for Nanopore MinION on 12 samples; however, this costing was limited to only some components and did not include human resource costs or overhead costs. For WGS (n=5), cost per sample ranged from US$ 63.00 on Nanopore MinION to US$ 277.00 on Illumina MiSeq; given that studies used an inconsistent number of component costs, comparisons were challenging. Based on the review, the most significant cost component was the sequencing step, and the largest component costs were reagents and consumables, including those necessary for sequencing, sample processing and targeted NGS steps library preparation. Study authors identified four major cost drivers: use of different sequencers, depth and breadth of coverage, inefficiencies in initial sample runs, and economies of scale via batching or cross-batching. The cost data from the systematic review were limited; therefore, an empirical unit", "costing was performed, in consultation with manufacturers and FIND. At the time of this work, only pricing for Deeplex Myc-TB was available and it was used for estimation of cost for the class. Unit costs included consumables, equipment, staffing and overheads (where available); also, costs assumed targeted NGS testing for all drugs. Based on the empirical analysis, the cost of targeted NGS was estimated to be: \u2022 US$ 134 to US$ 257 in South Africa; \u2022 US$ 120 to US$ 198 in Georgia; and \u2022 US$ 121 to US$ 175 in India.", "WHO consolidated guidelines on tuberculosis: Fourth edition 110 These costs are dependent on patient volume, batching and negotiated cost per targeted NGS kit. Recognizing the lack of economic evidence on this topic, a hypothetical cost\u2013effectiveness modelling study was undertaken to assess the cost\u2013effectiveness (Objective 1) and affordability (Objective 2) of these tests for the diagnosis of DR-TB in various high TB burden settings. Objective 1: To assess the potential cost\u2013effectiveness of introducing the targeted NGS technology for the diagnosis of DR-TB in Georgia, India and South Africa. This assessment included modelling the cost\u2013effectiveness of targeted NGS in three separate scenarios with distinct comparison options: a) Cost\u2013effectiveness of targeted NGS for DST among individuals with RR-TB after a rapid molecular test for rifampicin resistance as a replacement for phenotypic DST (PICO 2). b) Cost\u2013effectiveness of targeted NGS for DST among individuals with RR-TB after a rapid molecular test for rifampicin resistance as a replacement for current in-country DST practice (PICO 2). c) Cost\u2013effectiveness of targeted NGS as the initial test for TB drug resistance in patients with bacteriologically confirmed TB compared with rapid molecular testing for drug resistance and phenotypic DST in a high DR-TB burden setting (PICO 1). In the first scenario, targeted NGS was compared with universal phenotypic DST; in the second scenario, targeted NGS was compared with current in-country phenotypic DST practice among individuals with detected rifampicin resistance (PICO 2). This was done across three countries: Georgia, India and South Africa. Current DST practice in Georgia and South Africa includes Xpert XDR\u00ae followed by phenotypic DST; in India it includes LPAs and phenotypic DST done in parallel. A final scenario included targeted NGS compared to rapid molecular testing for drug resistance and phenotypic DST as initial tests for TB drug resistance among all TB patients (PICO 1) but was modelled for only one setting, Georgia \u2013 a high DR-TB burden setting. Epidemiological data were sourced from published literature; targeted NGS diagnostic accuracy data were sourced from the systematic review and IDP analysis conducted for this guideline. Economic data were sourced from published literature and a systematic and scoping review done in parallel by our team and supplemented with empirical data collection. A decision analysis modelling approach was used to estimate the incremental cost\u2013effectiveness of using targeted NGS for the diagnosis of DR-TB compared with various existing DST scenarios. This was done from the perspective of the health care", "system and accounts only for the health care system costs required to diagnose and treat TB. The estimation did not account for societal costs, or any direct or indirect costs incurred by patients. In addition, costs for sample transportation were not included in this analysis. The primary outcome was the incremental cost\u2013effectiveness ratio (ICER), which was calculated as the incremental cost in US dollars per disability-adjusted life year (DALY) averted. Main findings for PICO 1: Using targeted NGS as an initial test Using targeted NGS as an initial test for DST in the high DR-TB burden setting of Georgia led to more health gains (DALYs=0.49) compared with Xpert MTB/RIF or Xpert Ultra, followed by", "2. Recommendations for diagnosis of TB disease 111 phenotypic DST (DALY=0.51). The ICER per DALY averted was US$ 9261 (95% uncertainty range [UR]: US$ 5258\u201332 040/DALY averted), which was considered cost effective at a willingness- to-pay (WTP) threshold of three times the country GDP per capita (US$ 15 609), with 80% of simulated iterations falling below the WTP threshold. Main findings for PICO 2: Using targeted NGS among those with RR-TB Using targeted NGS as a replacement for universal phenotypic DST among RR-TB patients, targeted NGS was dominated by phenotypic DST, with targeted NGS having higher costs and leading to fewer health gains. This finding was driven by the high diagnostic accuracy of phenotypic DST (which was assumed to be universal in this scenario), and an assumption of no difference in loss to follow-up between targeted NGS and phenotypic DST. When in-country DST practice was used as the comparator (instead of universal phenotypic DST), targeted NGS led to more health gains than in-country DST across all three countries. Targeted NGS was cost effective in South Africa (ICER: US$ 15 619/DALY averted, 95% UR: cost saving \u2013US$ 114 782, at a WTP threshold of US$ 21 165), but was not cost effective in Georgia (ICER: US$ 18,375/ DALY averted, UR: cost saving \u2013US$ 158 972/DALY averted, at a WTP threshold of US$ 15 065). In India, where LPA, liquid culture and DST are being used as part of in-country DST, targeted NGS dominated the country\u2019s current DST practice, with lower costs and more health gains (95% UR: cost saving \u2013US$ 60 083). Main findings: scenario analyses Several key scenario analyses were investigated. In the base case approach, loss to follow-up was assumed to be equivalent between phenotypic DST and targeted NGS; in a scenario where there was no loss to follow-up in targeted NGS compared with 10% in phenotypic DST, targeted NGS was cost effective in South Africa (ICER: US$ 13 004/DALY averted, WTP: US$ 21 165) and Georgia (ICER: US$ 13 640/DALY averted, WTP: US$ 15 069) and targeted NGS still dominated in-country DST practice in India. In scenarios where sequencing platforms are used for multiple different diseases to reduce the unit test cost of targeted NGS, the cost\u2013effectiveness of targeted NGS improves in all three countries. A batching scenario was investigated, with an assumed 20% fewer samples per targeted NGS run, and led to an increased unit test cost", "for targeted NGS; in this scenario, the targeted NGS approach retained cost\u2013effectiveness only in South Africa. When a 50% price reduction in targeted NGS test kit cost was assumed, targeted NGS cost\u2013effectiveness further improved in all countries. Objective 2: To assess the financial impact of introducing targeted NGS as a replacement for existing DST for diagnosis of DR-TB among TB patients across three countries: Georgia, India and South Africa. A budget impact assessment was undertaken to estimate the financial consequences of adopting targeted NGS for DST for all patients diagnosed with TB, and replacing in-country DST practice in Georgia (PICO 1). The analysis suggested that implementing targeted NGS for all patients diagnosed with TB would be more expensive than testing all patients with Xpert MTB/RIF or Xpert Ultra, followed by phenotypic DST (see Fig. 2.4.5.2).", "WHO consolidated guidelines on tuberculosis: Fourth edition 112 Fig. 2.4.5.2 Budget impact assessment results comparing current standard practice for DST with implementation of targeted NGS for all patients diagnosed with TB in Georgia DST: drug susceptibility testing; NGS: next-generation sequencing; pDST: phenotypic DST; TB: tuberculosis; tNGS: targeted NGS. A budget impact assessment was undertaken to estimate the financial consequences of adopting targeted NGS for DST after a rapid molecular test for rifampicin resistance, and replacing in-country DST practice in Georgia, India and South Africa (PICO 2). In-country DST practice included Xpert XDR combined with phenotypic DST in Georgia and South Africa, and Xpert XDR combined with LPA in Georgia over a 1-year and 5-year period. It was assumed that the eligible RR-TB patient populations requiring DST were 58 837, 8200 and 187 in South Africa, India and Georgia, respectively, and that the TB reduction rate over the 5 years was stable (2). To estimate the impact on the country-specific budget, the economic costs generated by the model were multiplied by the number of patients. Results from a 1-year budget impact assessment for PICO 2 are presented in Fig. 2.4.5.3 In India, it was estimated that implementing targeted NGS would cost about US$ 57 130 727 \u2013 slightly lower than the current practice of LPA combined with phenotypic DST, which has a cost of US$ 57 719 097. In South Africa, it was estimated that implementing targeted NGS would result in a rise in budget to about US$ 27 888 200, slightly more than LPA combined with phenotypic DST, which has a cost of US$ 26 428 600. Finally in Georgia, where there are fewer bacteriologically confirmed patients, it was estimated that implementing targeted NGS would cost about US$ 592 221, slightly more than LPA combined with phenotypic DST, which has a cost of US$ 568 480. Total budget impact costs Year 1 budget impact $400 000 $350 000 $300 000 $250 000 $200 000 $150 000 $100 000 $50 000 $0 $220 660 $257 499 $220 660.00 $257 499.00 Xpert + pDST Georgia tNGS", "2. Recommendations for diagnosis of TB disease 113 Fig. 2.4.5.3 Budget impact assessment results comparing current standard practice for DST to implementing targeted NGS for patients with RR-TB in India, South Africa and Georgia DST: drug susceptibility testing; LPA: line probe assay; NGS: next-generation sequencing; pDST: phenotypic DST; RR-TB: rifampicin-resistant TB; TB: tuberculosis; tNGS: targeted NGS. User perspective A rapid review was commissioned to identify and synthesize qualitative evidence on the use of targeted NGS for the detection of TB drug resistance; in particular, the aim was to examine the implementation considerations related to acceptability, feasibility, and values, preferences and equity. The review searched Medline with no year or language limits. The search was run on 19 August 2022, and then rerun on 10 October 2022 to include WGS-related studies for the detection of TB drug resistance. The review did not identify any eligible studies for analysis and synthesis. Based on the systematic search, three records were identified; in addition, based on the open, hand and expert searches, 27 records were found. On full-text review of the 30 records, none were found to be eligible for inclusion. Given that no direct evidence was found, note was made of a Cochrane qualitative evidence synthesis published in 2022 that examined recipient and provider perspectives on rapid molecular tests for TB and drug resistance (52); that study provides relevant (though indirect) evidence on the subject. The authors noted that people with TB valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays and keeping diagnostic associated costs low, whereas health care providers valued aspects of accuracy and the resulting confidence in low complexity NAAT results, rapid turnaround times and low costs to people seeking a diagnosis. To address the direct evidence gap, WHO commissioned an additional qualitative cross-sectional study comprising semi-structured interviews, primarily with laboratory staff and management personnel directly involved with implementing targeted NGS in the three FIND trial sites, as well as with three global experts involved in TB care and diagnostics. In total, there were 17 respondents, and the work was conducted during September to October 2022. The objective was to explore the perceptions and experiences of those implementing targeted NGS technology, with respect to acceptability, feasibility, and values, preferences and equity. The main findings are summarized below. Year 1 budget impact Total budget impact costs $70 000 000 $60 000 000 $50 000 000 $40 000 000 $30", "WHO consolidated guidelines on tuberculosis: Fourth edition 114 Acceptability A consistently positive sentiment was expressed for the acceptability and potential utility of targeted NGS technology. Targeted NGS was seen as a \u201cmajor advancement\u201d in molecular MDR-TB diagnostics. 1. The main reasons for the high level of acceptability were the comprehensiveness (resistance diagnosis for more drugs and for the newest and repurposed drugs), the convenience of using a sputum sample (as compared with culture samples), and the rapidity (quick results compared with phenotypic testing times; 3\u20135 days as compared with 4\u20136 weeks). 2. There was also the sense that there is a good window of opportunity to benefit from the utility of targeted NGS technology; that is, the technology is arriving at the right time, given that resistance to newer TB drugs is likely to increase as the use of these drugs becomes routine. Feasibility Although there was high praise for the capability and potential utility of targeted NGS technology, several challenges were identified when testing samples using the targeted NGS platforms, which may limit the feasibility of targeted NGS for routine uptake at the present time. The overall sentiment was that the targeted NGS technology needs to be further developed before it can be considered fully ready for operational use. The following feasibility challenges were identified: \u2022 Start-up and setting-up challenges: Multiple problems were identified with starting and setting up the technology. These problems related to the newness of the technology and the trial setting, importing technology and specialist supplies, lack of in-country technical assistance for problem-solving and need for more hands-on training practice. \u2022 High technical complexity of the test: Targeted NGS technology was seen as a high complexity molecular test that was technically challenging. For example, preparing the sample for sequencing involves multiple steps that require attention to detail and precision, leaving little room for error. Preparation of the library is particularly complex for the Deeplex platform, although both the Deeplex and the Nanopore platforms are quite complex. In both platforms, it was thought that there were too few opportunities for early recognition and correction of errors, increasing the risk of failed runs. \u2022 Specialized laboratory infrastructure and human resource requirements: Because targeted NGS is a molecular-based testing platform, it requires highly specialized laboratory infrastructure (e.g. multiple rooms to prevent amplicon contamination and specialized cold storage facilities). Also, highly specialized molecular and medical scientists are needed to perform", "the tests. In LMIC settings, such specialized laboratory infrastructure and staff may only be available at centralized laboratories (i.e. not at regional laboratories). \u2022 Special requirements for operating the test: In addition to highly specialized laboratory infrastructure and staff, the testing technology also requires an uninterrupted supply of electricity, high internet connectivity, high computer capacity, clean water and temperature controls \u2013 requirements that may pose challenges in some LMIC settings.", "2. Recommendations for diagnosis of TB disease 115 \u2022 Supply chain challenges: Major challenges were reported relating to the required supply chain for implementing targeted NGS. Procurement bottlenecks and delays coupled with shelf-life limitations of reagents jeopardize continuous access to specialist supplies. \u2022 Data management and storage requirements: There were concerns that data analysis and data storage requirements were not fully developed, including systems for backing up data, ownership of data and security of data. Another issue that needs to be considered is how targeted NGS and routine laboratory information systems can be interlinked. \u2022 Continuous updating of the WHO catalogue of mutations is required: There was agreement that the usefulness of the targeted NGS technology depends on the informational support provided by the WHO catalogue of mutations (53), which allows for meaningful interpretation of resistance data; thus, there is a need for the WHO catalogue to be continuously updated. \u2022 Feasibility concerns differed for the different targeted NGS platforms: The overall sentiment was that all targeted NGS platforms needed to be further developed before they are fully ready for operational use, some more than others. The high level of technical complexity of the sample preparation stages (mainly the library preparation stage) was considered a key challenge for the Deeplex platform, and the need for improved computer analysis and storage capacity was a challenge for the Oxford Nanopore platform, although both required a high level of precision and attention to detail. There is also a need to incorporate steps for early error recognition. Values, preferences and equity The overall sentiment is that MDR-TB diagnostic technology needs to balance accuracy, speed, affordability, equity and cost\u2013effectiveness, and that targeted NGS technology would need to address these considerations before it can be implemented in LMIC settings. These considerations were consistent across the different stakeholder groups who participated in the study. 1. Centralized versus decentralized placement may have equity implications for access: Given the high-level specialized laboratory infrastructure, specialized human resources and technical complexity needed for targeted NGS, the technology may be suitable for placement only at centralized, reference laboratories. This may have equity access considerations if it means less access for some regions of a country that lack reference laboratories. This may also have implications for costs (e.g. costs for transport of sputum), probability of sample loss and time to results. 2. Affordability and cost\u2013effectiveness are major concerns: There was a major concern", "about the financial costs of the targeted NGS technology and the affordability for LMIC. Participants were worried about the cost of the equipment and the costs of ongoing specialist supplies (especially reagents), as well as the cost of maintaining equipment. They noted that costing calculations should be comprehensive and should include the cost of special consumables, extra general laboratory consumables and additional infrastructure needs (e.g. extra space, temperature control and internet connectivity). There were concerns that cost\u2013effectiveness calculations should be comprehensive and should include assessment of the impact of the use of targeted NGS testing on improving TB outcomes.", "WHO consolidated guidelines on tuberculosis: Fourth edition 116 3. The MDR/RR-TB case burden of a country could influence equitable access at centralized levels. In some settings with high caseloads, the targeted NGS technology capacity in central laboratories may not be sufficient for processing large caseloads in good time; also, in settings with low caseloads, waiting for sufficient samples to batch-test will cause delays. Implementation considerations Although the evidence that is available supports the use of targeted NGS to detect drug resistance after TB diagnosis, to guide clinical decision-making for DR-TB treatment, the following factors need to be considered when implementing these tests: \u2022 Regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of these diagnostic tests. \u2022 In its current format, targeted NGS is a high complexity test that is most suitable for centralized laboratories equipped with specialized skills and infrastructure. \u2022 Targeted NGS tests do not replace existing rapid tests that are more accessible and easier to perform for detecting resistance to rifampicin, isoniazid and fluoroquinolones. However, if targeted NGS can be performed rapidly, it can be considered as an alternative initial option for prioritized populations. Those who will benefit most from these tests are individuals who require rapid and comprehensive DST but have limited access to phenotypic DST. \u2022 Priority should be given to samples with a high bacillary load as determined by initial bacteriological tests (e.g. semiquantitative high/medium or smear-positive grading). In situations where the bacillary load is low (e.g. semiquantitative low/very low/trace or smear- negative grading), the recommendations still hold, although rates of indeterminate results are likely to be higher; therefore, phenotypic DST is likely still required for samples with a low bacillary load. \u2022 Similarly, the recommendations apply to children, adolescents and PLHIV populations because these populations have a higher frequency of samples with low bacterial load. \u2022 The recommendation is based on data obtained from sputum and BAL specimens, and can be extrapolated to other lower respiratory tract samples (e.g. endotracheal aspirates). However, further research is needed to evaluate the use of these tests on alternative sample types for diagnosing pulmonary TB in children (e.g. nasopharyngeal and stool samples) and diagnosing extrapulmonary TB. \u2022 Since sensitivity for bedaquiline, linezolid and clofazimine resistance is suboptimal, consideration of the pretest probability is important in interpreting the targeted NGS results for these drugs. Further testing of samples with a susceptible result (using", "culture- based phenotypic DST) would be warranted, particularly when the risk of resistance is high. Since specificity is high, a result that indicates resistance may be used to guide the therapy, particularly among those at risk for resistance. In the case of pretomanid, the basis for resistance has not been fully elucidated; hence, culture-based DST is also required for this drug.", "2. Recommendations for diagnosis of TB disease 117 Research priorities Several key research priorities emerged from the reviews of the available evidence on targeted NGS for detecting TB drug resistance. They fall into three main categories: clinical research, implementation research, and monitoring and evaluation. Clinical research: \u2022 Conduct clinical trials to assess the impact of targeted NGS on patient-important outcomes14. \u2022 Evaluate the accuracy and impact on patient-important outcomes of targeted NGS among populations of individuals diagnosed with TB, across a range of prevalences of rifampicin or other drug resistance). \u2022 Assess the accuracy and impact on patient-important outcomes of targeted NGS for detecting resistance to new and repurposed drugs, including pretomanid, across varied geographical and epidemiological settings. \u2022 Assess the accuracy and impact on patient-important outcomes of targeted NGS for analysing extrapulmonary samples, including CSF for meningitis, non-sputum samples (e.g. nasopharyngeal aspirate, gastric aspirate or stool) for children, and alternative sample types (e.g. tongue swabs) in both adults and children. \u2022 Undertake additional qualitative and quantitative research to further understand the perspectives of end-users and clinicians regarding the acceptability and feasibility of using targeted NGS. Implementation research: \u2022 Develop and evaluate effective and efficient implementation models by integrating targeted NGS into laboratory networks and optimizing algorithms, with the aim of enhancing timely access to testing and treatment initiation, and improving patient outcomes. \u2022 Develop strategies to enhance the efficiency of targeted NGS testing, including sample processing and concentration techniques, determining optimal thresholds of bacterial load from initial tests before performing targeted NGS, and employing molecular transport medium for the ambient storage and transfer of samples to testing sites. \u2022 Regularly update the WHO catalogue of mutations (53), incorporating additional genetic targets and including new drugs (e.g. pretomanid) to enhance the sensitivity and specificity of targeted NGS. \u2022 Explore technological advancements to simplify the testing process, automate steps (especially library preparation), develop decentralized targeted NGS solutions and investigate potential synergies with existing initial tests (e.g. using leftover DNA or smear-positive slides). \u2022 Conduct comprehensive mapping of sequencing capacity within countries and perform diagnostic network optimization exercises. Placement of the technology should consider the demand for sequencing across multiple diseases, facilitating cross-disciplinary use of the machines and shared costs. \u2022 Compile and use lessons learned from applying targeted NGS technology in other diseases (e.g. COVID-19) to develop effective implementation strategies for TB. 14 Mortality, Cure, Lost to follow up; Time to", "WHO consolidated guidelines on tuberculosis: Fourth edition 118 Monitoring and evaluation: \u2022 Standardize the nomenclature for reporting of results across different targeted NGS technologies, for integration into health information data systems. \u2022 Ensure separate recording of true failures and unclassified mutations, and monitor trends over time as an essential component of result reporting. \u2022 Regularly monitor performance data, including overall resistance rates, resistance rates by specific drugs or targets and turnaround times (both total and in-laboratory). \u2022 Incorporate quality monitoring measures, such as tracking indeterminate rates, sequencing coverage and depth, and participating in external quality assurance programmes. \u2022 Establish an external quality assurance programme for sequencing that covers all relevant targets of interest. \u2022 Integrate the sequencing data generated into existing surveillance systems to monitor the prevalence and trends in drug resistance effectively. Share the data to update the WHO mutation catalogue. \u2022 Collect cost data to address important questions, such as the costs associated with introducing and scaling up targeted NGS in different settings, the trade-offs between turnaround time and batching, and the optimal balance in various settings. \u2022 Assess the impact of multidisease testing on programme operations and costs, including disease-specific testing volumes, turnaround times, costing, resource sharing and resource requirements. \u2022 Evaluate the impact of time to treatment initiation or modification, treatment outcomes and overall cost\u2013effectiveness of targeted NGS implementation.", "2. Recommendations for diagnosis of TB disease 119 2.5. References 1. Global tuberculosis report 2024. Geneva: World Health Organization; 2024 (https://www.who.int/ teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2024). 2. Resolution 78/L.4. Political declaration of the high-level meeting of the General Assembly on the fight against tuberculosis. New York: United Nations; 2023 (https://digitallibrary.un.org/record/4022582). 3. Implementing the End TB Strategy: the essentials. Geneva: World Health Organization; 2015 (https:// apps.who.int/iris/handle/10665/206499). 4. Boyer S, March L, Kouanfack C, Laborde-Balen G, Marino P, Aghokeng AF, Mpoudi-Ngole E, Koulla-Shiro S, Delaporte E, Carrieri MP, Spire B, Laurent C, Moatti JP; Stratall ANRS 12110/ESTHER Study Group. Monitoring of HIV viral load, CD4 cell count, and clinical assessment versus clinical monitoring alone for antiretroviral therapy in low-resource settings (Stratall ANRS 12110/ESTHER): a cost-effectiveness analysis. Lancet Infect Dis. 2013 Jul;13(7):577\u201386. doi: 10.1016/S1473\u2013 3099(13)70073\u20132. Epub 2013 Apr 18. PMID: 23602084. 5. Eckman MH, Ward JW, Sherman KE. Cost effectiveness of universal screening for hepatitis C virus infection in the era of direct-acting, pangenotypic treatment regimens. Clin Gastroenterol Hepatol. 2019;17:930\u20139. e9. doi: https://doi.org/10.1016/j.cgh.2018.08.080. 6. Wang J-H, Chen C-H, Chang C-M, Feng W-C, Lee C-Y, Lu S-N. Hepatitis C virus core antigen is cost- effective in community-based screening of active hepatitis C infection in Taiwan. J Formos Med Assoc. 2020;119:504\u20138. doi: https://doi.org/10.1016/j.jfma.2019.07.011. 7. Report for WHO: non-inferiority evaluation of Nipro NTM+MDRTB and Hain GenoType MTBDRplus V2 line probe assays. Geneva: Foundation for Innovative New Diagnostics; 2015. 8. Nathavitharana RR, Cudahy PG, Schumacher SG, Steingart KR, Pai M, Denkinger CM. Accuracy of line probe assays for the diagnosis of pulmonary and multidrug-resistant tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2017;49:1601075. doi: https://doi. org/10.1183/13993003.01075\u20132016. 9. Rapid diagnosis of tuberculosis brochure. Nehren, Germany: Hain Lifescience; 2015 ( http://www. hain-lifescience.de/uploadfiles/file/produkte/mikrobiologie/mykobakterien/tb_eng.pdf). 10. Bossuyt P, Reitsma J, Bruns D, Gatsonis C, Glasziou P, Irwig L et al. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ. 2015;351:h5527. doi: https://doi. org/10.1136/bmj.h5527. 11. Sekiguchi J, Nakamura T, Miyoshi-Akiyama T, Kirikae F, Kobayashi I, Augustynowicz-Kopec E et al. Development and evaluation of a line probe assay for rapid identification of pncA mutations in pyrazinamide-resistant Mycobacterium tuberculosis strains. J Clin Microbiol. 2007;45:2802\u20137. doi: https://doi.org/10.1128/jcm.00352\u201307. 12. K\u00f6ser CU, Cirillo DM, Miotto P. How to optimally combine genotypic and phenotypic drug susceptibility testing methods for pyrazinamide. Antimicrob Agents Chemother. 2020;64:e01003\u2013 20. doi: https://doi.org/10.1128/AAC.01003\u201320. 13. Groessl EJ, Ganiats TG, Hillery N, Trollip A, Jackson RL, Catanzaro DG et al. Cost analysis of rapid diagnostics", "for drug-resistant tuberculosis. BMC Infect Dis. 2018;18:102. doi: https://doi.org/10.1186/ s12879\u2013018\u20133013\u20130. 14. Li X, Deng Y, Wang J, Jing H, Shu W, Qin J et al. Rapid diagnosis of multidrug-resistant tuberculosis impacts expenditures prior to appropriate treatment: a performance and diagnostic cost analysis. Infect Drug Resist. 2019;12:3549\u201355. doi: https://doi.org/10.2147/idr.S224518. 15. GRADEpro GDT [website]. Hamilton, Ontario: McMaster University; 2020 (https://gradepro.org/).", "121 3. Recommendations for diagnosis of TB infection 3.1. Mycobacterium tuberculosis antigen-based skin tests for the diagnosis of TB infection Since 2011, the World Health Organization (WHO) has issued recommendations on the use of IGRAs for the diagnosis of TB infection. In 2018, WHO updated the recommendations to stipulate that the TST or IGRAs (or both) can be used to test for TB infection in LMIC. The TST is a widely used point-of-care test that involves intradermal injection of purified protein derivative (PPD), a crude mixture of different mycobacterial antigens, which stimulates a delayed-type hypersensitivity response and causes induration at the injection site within 48\u201372 hours. This test has relatively low specificity in those with recent bacille Calmette-Gu\u00e9rin (BCG) vaccination and low sensitivity in immunosuppressed individuals (e.g. people living with HIV [PLHIV]); hence, interpretive cut-offs must be adapted for these populations. A follow-up clinic visit is required after the placement of the TST, and results must be read within the suggested time frame to be valid. In contrast, IGRAs are in vitro tests that measure release of interferon- gamma (IFN-\u03b3) by T-cells following stimulation by the early secretory antigenic target 6 kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10) antigens that are specific to Mtb. Unlike the TST, IGRAs are not affected by prior BCG vaccination, or by infection with nontuberculous mycobacteria (NTM), with few exceptions. However, IGRA platforms are more expensive to run and require specialized facilities and trained personnel; consequently, the TST is the most commonly used test for TB infection globally. Recent global shortages of PPD have underscored the need for alternatives. In addition to the TB skin tests and interferon gamma release assays previously recommended by WHO, Mtb antigen-based skin tests (TBSTs) based on specific antigens have recently been developed, using the same ESAT-6 and CFP-10 antigens; these tests combine the simpler skin- test platform with the specificity of IGRAs. TBSTs include the Cy-Tb (Serum Institute of India, India), Diaskintest\u00ae (Generium, Russian Federation) and C-TST (formerly known as ESAT6-CFP10 test, Anhui Zhifei Longcom, China). All tests use intradermal injection of antigen and, like the TST, are read after 48\u201372 hours as induration in millimetres, using the method suggested by Mantoux. Emerging evidence suggests that, compared with IGRAs, the tests may have similar specificity and provide more reliable results in children and adolescents as well as in PLHIV than the TST. However, the evidence had not", "WHO consolidated guidelines on tuberculosis: Fourth edition 122 data on diagnostic accuracy, safety, economic aspects and qualitative evidence on feasibility, acceptability, equity, end-user values and preferences. A Guideline Development Group (GDG) was convened by WHO from 31 January to 3 February 2022, to discuss the findings of the systematic reviews and to make recommendations on this class of diagnostic technologies for TB infection. The following technologies were included in the evaluation: \u2022 Cy-Tb (Serum Institute of India, India); \u2022 Diaskintest (Generium, Russian Federation); and \u2022 C-TST (formerly known as ESAT6-CFP10 test, Anhui Zhifei Longcom, China) Table 3.1.1 PICO questions for assessment of TBSTs Population Intervention Comparator Outcome y PLHIV y Children aged <5 years y Household and other close contacts y Other at-risk groups: y Immune compromised (e.g. individuals receiving anti-TNF-\u03b1 treatment \u2013 or dialysis; individuals undergoing preparation for an organ or haematological transplant; patients with silicosis; pregnant women; or individuals who are malnourished, have diabetes mellitus, use steroids or smoke tobacco) \u2013 High risk of prior TB exposure (e.g. prisoners, health workers, immigrants from high TB burden countries, individuals with CXR abnormalities, homeless people and people who use drugs, and inhabitants of high TB burden settings)a y BCG-vaccinated versus non- vaccinated (in identified groups at risk of TB infection \u2013 stratified or in combination, as appropriate) y TBSTs: y Diaskintest y Cy-Tb y C-TST y Others TST or IGRAs y Efficacy of TPT based on diagnostic test results y Predictive value for progression to TB disease y Correlation with exposure gradient y Sensitivity and specificityb for TB infectionc y Concordance with the TST y Concordance with IGRAs y Proportion started on TPT", "3. Recommendations for diagnosis of TB infection 123 The current recommendations are based on the evaluation of data for the tests that were included in the present evaluation. The findings cannot be extrapolated to other brand-specific tests; also, any new in-class technologies will need to be specifically evaluated by WHO. Guidelines are disseminated through the WHO Global TB Programme (WHO/GTB) listservs to WHO regional offices, Member States, the Stop TB Partnership and other stakeholders (e.g. the Global Laboratory Initiative and the TB Supranational Reference Laboratory Network); they are also published on the websites of the WHO/GTB and Global Laboratory Initiative. The updated policy is incorporated into the WHO TB Knowledge Sharing Platform \u2013 an online reference resource for global TB policies and derivative products. Recommendation 18. Mycobacterium tuberculosis antigen-based skin tests (TBSTs) may be used to test for TB infection. (Conditional recommendation for the intervention, very low certainty of the evidence) Evidence base In 2021, WHO commissioned a systematic review of published and unpublished data on the new class of tests for TB infection not previously reviewed by WHO. The overarching policy question was: Should Mtb antigen-based skin tests (TBSTs) for TB infection be used as an alternative to the tuberculin skin test (TST) or WHO-endorsed interferon-y release assays (IGRA) to identify individuals most at risk of progression from TB infection to TB disease? Based on the ov erarching policy question, four domains for evidence search and generation were included: diagnostic accuracy, safety, economic aspects and qualitative aspects. For each domain, specific population, intervention, comparator and outcome (PICO) or research questions were defined. Domain 1 \u2013 Diagnostic accuracy (PICO question): Do TBSTs have similar or better diagnostic performance than the TST or IGRAs to detect TB infection? Domain 2 \u2013 Safety: Do TBSTs for TB infection cause more adverse reactions than the TST or IGRAs? \u2022 What is the risk of adverse events of TBSTs compared with the current TST or IGRAs? \u2022 Consider data on both local and systemic reactions graded by type, severity and seriousness, and stratified by subgroup. \u2022 Compute relative risks where possible; however, if there is no control group receiving a comparator test, report frequency (%) of adverse events. Domain 3 \u2013 Cost\u2013effectiveness analysis: What are economic considerations of TBSTs compared with the TST or IGRAs? \u2022 How large are the resource requirements (costs)? \u2022 What is the certainty of the evidence on resource requirements", "WHO consolidated guidelines on tuberculosis: Fourth edition 124 Domain 4 \u2013 User perspective: What are end-user4 views and perspectives on use of novel skin-based in vivo tests for TB infection use? \u2022 Is there important uncertainty about, or variability in, how much end-users value the main outcomes? \u2022 What would be the impact on health equity? \u2022 Is the intervention acceptable to key stakeholders? \u2022 Is it feasible to implement the intervention? The certainty of the evidence of the pooled studies was assessed systematically through PICO questions, using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (2, 3). The GRADE approach produces an overall quality assessment (or certainty) of evidence, and has a framework for translating evidence into recommendations; also, under this approach, even if diagnostic accuracy studies are of observational design, they start as high-quality evidence. GRADEpro Guideline Development Tool software (4) was used to generate summary of findings tables. The quality of evidence was rated as high (not downgraded), moderate (downgraded one level), low (downgraded two levels) or very low (downgraded more than two levels), based on five factors: risk of bias, indirectness, inconsistency, imprecision and other considerations. The quality (certainty) of evidence was downgraded by one level when a serious issue was identified and by two levels when a very serious issue was identified in any of the factors used to judge the quality of evidence. For data from the systematic reviews that were of a qualitative nature, the GRADE-CERQual tool was used. The tool examines the methodological limitations of the included studies, the coherence of each review finding, the adequacy of the data in support of a review finding and the relevance of the included studies to the review research questions; it is used to assess data quality from qualitative research studies. Data synthesis was structured around the preset PICO question, as outlined above. The following web annexes provide additional information to evidence synthesis and analysis: \u2022 Web Annex A. Accuracy of Mycobacterium tuberculosis antigen-based skin tests: a systematic review and meta-analysis \u2022 Web Annex B. Safety of Mycobacterium tuberculosis antigen-based skin tests: a systematic review and meta-analysis \u2022 Web Annex C. GRADE profiles of Mycobacterium tuberculosis antigen-based skin tests \u2022 Web Annex D. Cost\u2013effectiveness of Mycobacterium tuberculosis antigen-based skin tests: a systematic review \u2022 Web Annex E. Modelling for economic evidence for the use of Mycobacterium tuberculosis antigen-based skin tests \u2022 Web Annex", "3. Recommendations for diagnosis of TB infection 125 Diagnostic accuracy Diagnostic accuracy studies evaluating sensitivity, specificity and concordance (agreement) of TBSTs were identified. There were no identified studies on the efficacy of TPT based on diagnostic test results, on the predictive value for progression to TB disease or on the proportion started on TPT. The assessed evidence for Cy-Tb and C-TST has included a manufacturer-recommended induration of at least 5 mm as the cut-off. According to the Diaskintest instructions for use, the presence of induration of any size is considered a positive response. However, the assessed evidence also included some studies for Diaskintest that used an induration of at least 5 mm as a cut-off, specified where applicable. Sensitivity A total of 20 studies involving 1627 participants provided data for evaluating the sensitivity of TBSTs in people with microbiologically confirmed TB, which was used as a proxy for sensitivity to diagnose TB infection. Of these, six studies with 539 participants were head-to-head comparisons with the TST or IGRAs (or both); 17 studies included 1276 participants who were HIV-negative or whose HIV status was unknown; five studies included 317 PLHIV; and four studies included 34 participants aged under 18 years. Of the included studies, 14 evaluated Diaskintest, four Cy-Tb and three C-TST, as shown in Figs. 3.1.1.1\u20133.1.1.2. Fig. 3.1.1.1 Sensitivity of TBSTs in head-to-head studies", "WHO consolidated guidelines on tuberculosis: Fourth edition 126 The pooled sensitivity against the microbiological reference standard for TB disease in six head- to-head studies ( Fig. 3.1.1.1) was 78.1% (95% confidence interval [CI]: 70.6\u201384.1%). The evidence was considered to be of high certainty and was not downgraded. Starshinova 2018 (5) and Starshinova 2019 (6) evaluated Diaskintest results with a cut-off of induration of at least 5 mm; the rest of the studies were head-to-head studies evaluating Cy-Tb. The assessed evidence for Cy-Tb included a cut-off of at least 5 mm in all studies. The TST cut-off was 5 mm for PLHIV and 15 mm for people who were HIV-negative in four studies (7\u201310). Only studies on Diaskintest and Cy-Tb were included in this analysis. Fig. 3.1.1.2 Sensitivity of TBSTs in all studies in individuals with HIV-negative or unknown status The pooled sensitivity in 17 studies presented in Fig. 3.1.1.2 among participants who were HIV- negative or HIV status unknown was 76.0% (95% CI: 70.3\u201380.8%). The sensitivity estimates were lower in the studies using Diaskintest (any induration size). The reason for this is unclear; it may reflect different study populations or study quality. As a result, the evidence certainty was downgraded one level for inconsistency and another level for imprecision. Consequently, the certainty of the evidence was considered very low. Despite the manufacturer\u2019s recommendation to use induration of any size as a positive result, the sensitivity in studies using a Diaskintest result of at least 5 mm as the cut-off was more closely aligned with the other tests in the class, which all use a cut-off of at least 5 mm.", "3. Recommendations for diagnosis of TB infection 127 Risk of bias was considered serious due to the person having knowledge of the reference standards when interpreting the results of index tests. In most Diaskintest studies, the selection of participants and of the reference standard were unclear; hence, the certainty of the evidence was downgraded one level for risk of bias. The sensitivity ranged from 55% to 100% (the reasons for this heterogeneity are unknown); consequently, the certainty of the evidence was downgraded one level for inconsistency. Thus, the overall certainty of the evidence was considered low. Fig. 3.1.1.3 Sensitivity of TBSTs in PLHIV Only studies on Diaskintest and Cy-Tb were included in the analysis presented in Fig. 3.1.1.3 The pooled sensitivity among PLHIV in five studies was 63.5% (95% CI: 52.6\u201373.2%). Risk of bias was considered serious for Diaskintest studies because of the person having knowledge of the reference standards when interpreting the results of index tests; hence, the evidence certainty was downgraded one level for risk of bias. The sensitivity estimates were lowest (39.8%) in the one study that used Diaskintest (any induration size). The reason for low sensitivity for Diaskintest (any induration size) is unclear, and the evidence certainty was downgraded one level for inconsistency. Certainty was also downgraded one level for imprecision. Consequently, the certainty of the evidence was considered to be very low. Fig. 3.1.1.4 Sensitivity of TBSTs in children and adolescents", "WHO consolidated guidelines on tuberculosis: Fourth edition 128 Sensitivity of TBSTs among children and adolescents is shown in Fig. 3.1.1.4 . The pooled sensitivity in four studies for this class of tests was 97.1% (95% CI: 81.9\u201399.6%). The number of participants included in this analysis was small \u2013 only 34 participants in four studies; hence the studies were downgraded two levels for imprecision. Therefore, the evidence certainty was considered low. Only studies on Diaskintest were available for this analysis. Aggerbeck (7) estimated the sensitivity of Cy-Tb in 12 children and adolescents with TB, of whom only two were bacteriologically confirmed and were not included in the figure. Specificity A total of 14 studies involving 3792 participants provided data for evaluating specificity of TBSTs (including difference in specificity compared with the reference test); three of the studies included 1104 children and adolescents and three included 587 BCG-vaccinated individuals. Specificity was measured in healthy individuals with negative IGRA results. Difference in specificity was used as an alternative specificity measure, and was calculated as the difference in the proportion of negative results between TBSTs and the TST or IGRAs in healthy populations. Fig. 3.1.1.5 Specificity in healthy individuals with negative IGRA results The specificity assessed in the five studies presented in Fig. 3.1.1.5 was high for all three tests in the TBST class. For Diaskintest it was 99.1% (95% CI: 93.6\u201399.9%), as compared with QFT; for Cy-Tb it was 98.0% (95% CI: 92.6\u201399.5%), as compared with QFT; and for C-TST it was 95.5% (95% CI: 92.6\u201397.3%), as compared with T-Spot. During the GDG meeting, participants noted that \u2013 considering the totality of evidence (which included studies of very low quality) \u2013 the overall certainty of the evidence on tests\u2019 effects for specificity was very low. Specificity in children and adolescents (2 studies, 176 patients), as determined in individuals with negative IGRA results, was high. For Diaskintest with a cut-off of at least 5 mm it was 99.1% (95% CI: 94.9\u201399.9%), as compared with QFT, and for Cy-Tb it was 91.4% (95% CI: 82.2\u201396.1%), as compared with QFT. Specificity in BCG-vaccinated individuals (3 studies, 292 patients), as determined in healthy individuals with negative IGRA results, was also high, being 97\u201399% (depending on the test), with a pooled value of 99.0% (95% CI: 96.9\u201399.7%). More details can be found in Web Annex A.", "3. Recommendations for diagnosis of TB infection 129 Fig. 3.1.1.6 Difference in specificity \u2013 TBSTs versus the TST The overall pooled difference in specificity in 14 studies (Fig. 3.1.1.6) comparing TBSTs and the TST was 33.5% (95% CI: 18.2\u201348.8%) higher for TBSTs. In studies of Diaskintest and C-TST done in high TB incidence settings, the differences in specificity were higher for Diaskintest versus the TST (with both tests having a cut-off of at least 5 mm) (57.3%, 95% CI: 40.2\u201374.3%), than with Diaskintest (any induration size) versus the TST with a cut-off of at least 5 mm (29.9%, 95% CI: \u20133.66\u201363.5%). For C-TST versus the TST with a cut-off of at least 5 mm, the difference in specificity was 39.9% (95% CI: 34.0\u201345.8%). In contrast, in studies of Cy-Tb undertaken in low TB incidence settings, the difference in specificity between Cy-Tb and the TST was less prominent, but was greater with the TST with a cut-off of at least 15 mm (4.61%, 95% CI: \u201328.6\u201337.9%) than with the TST with a cut-off of 5 or 15 mm (\u20132.0%, 95% CI: \u201312.3\u20138.3%). The difference may be explained by the background level of BCG in the study populations or by the cut-offs that were used. Fig. 3.1.1.7 has more details on the specificity of TBSTs versus the TST in BCG-vaccinated people. Overall risk of bias was considered serious because test allocation by arm was not blinded in any of the studies except those for Cy-Tb. In most Diaskintest studies, the selection of participants and the diagnosis of the reference standard were unclear. The certainty of the evidence was therefore downgraded one level for risk of bias. The difference in specificity ranged from \u20132% to 72%; hence, the certainty of the evidence was downgraded one more level for inconsistency. Consequently, the certainty of the evidence for difference in specificity between TBSTs and the TST was low.", "WHO consolidated guidelines on tuberculosis: Fourth edition 130 Fig. 3.1.1.7 Difference in specificity \u2013 TBSTs versus the TST in BCG-vaccinated population Two studies (three analyses) provided data on difference in specificity in BCG-vaccinated populations, which was even higher for this population than in populations where only some people had received BCG vaccination; the pooled difference in specificity was 67.4% (95% CI: 24.0\u2013110.7%). Overall risk of bias was considered serious because test allocation by arm was not blinded; hence, the certainty of the evidence was downgraded one level for risk of bias. The CI was broad, ranging from 24.0% to 110.7%, so the certainty of the evidence was downgraded one more level for imprecision. Consequently, certainty of the evidence for difference in specificity between TBSTs and the TST in BCG-vaccinated populations was low. The pooled difference in specificity in six studies comparing TBSTs and IGRAs was low, at 2.3% (95% CI: \u20131.6\u20136.2%), meaning that TBSTs were similar to IGRAs in terms of specificity. Agreement Overall, 16 studies involving 3198 participants (among which four studies with 1307 participants recruited people aged under 18 years) were included to assess agreement of the index tests with comparator tests (the TST or IGRAs, or both). In participants without TB disease, agreement was high (\u226590%) for Cy-Tb and Diaskintest \u2013 (any induration size) and Diaskintest 5 mm induration \u2013 compared with QFT ( Fig. 3.1.1.8 ). Agreement was slightly lower at 85.5% (95% CI: 75.7\u201391.7%) for C-TST compared with T-Spot. In one study, which evaluated Diaskintest with induration of at least 7 mm compared with T-Spot, the agreement was considerably lower, at 60.9% (95% CI: 54.3\u201367.2%). Risk of bias was considered serious because the allocation of tests was not blinded in five studies; hence, certainty of the evidence was downgraded one level for risk of bias. Agreement ranged widely (from 61% to 97%) for various tests and studies, so the certainty of the evidence was downgraded one level for inconsistency. Consequently, certainty of the evidence for agreement between TBSTs and IGRAs was low.", "3. Recommendations for diagnosis of TB infection 131 Fig. 3.1.1.8 Agreement of TBSTs versus IGRAs in all studies including participants without active TB In participants with TB disease, high agreement between TBSTs and IGRAs as the comparator (85.7%) was observed ( Fig. 3.1.1.9 ). Some variability in agreement was seen between the different tests: 79.6% (95% CI: 76.3\u201382.6%) for Cy-Tb 5 mm compared with QFT; 97.3% (95% CI: 72.7\u201399.8%) for Diaskintest (any induration size) compared with QFT; and 97.0% (95% CI: 92.3\u2013 98.9%) for DST 5 mm induration compared with QFT. Agreement was slightly lower at 85.4% (95% CI: 72.4\u201392.9%) for C-TST compared with T-Spot. Risk of bias was considered serious because, in four studies, the allocation of tests by arm was not blinded; hence, the certainty of the evidence was downgraded one level for risk of bias. The agreement ranged from 75% to 100% for various tests and studies, so certainty of the evidence was downgraded one level for inconsistency. The overall certainty of the evidence for agreement between TBSTs and IGRAs in people with TB disease was considered low.", "WHO consolidated guidelines on tuberculosis: Fourth edition 132 Fig. 3.1.1.9 Agreement of TBSTs versus IGRAs in all studies including people with active TB Safety A systematic review of studies reporting the outcomes of interest, including local reactions \u2013 that is, injection site reactions (ISR) and systemic adverse events from TBSTs \u2013 was undertaken. The following databases were searched for studies from inception until 30 July 2021: Medline, Embase, e-library, the Chinese Biomedical Literature Database and the China National Knowledge Infrastructure Database. The test manufacturers were contacted for individual studies, and studies were identified through a public call for data by WHO. Longitudinal and case\u2013control studies reporting adverse events of the index tests alone or compared with recognized comparator tests (e.g. QFT, T-Spot and the TST) in humans were included with no language restrictions. Screening of titles and abstracts as well as full-text articles and the assessment of quality were performed by two investigators in duplicate. A meta-analysis was conducted using a random-effects model, and studies that were considered to be clinically homogenous were pooled. Overall, seven studies for Cy-Tb, five for C-TST and 11 for Diaskintest were identified. Characteristics of studies were as follows: \u2022 Cy-Tb: clinical trials \u2013 three studies in South Africa and four in Europe. Most participants were adults; in studies in South Africa, 20\u201340% of participants were PLHIV. Five of seven studies included random allocation of Cy-Tb versus the TST into two arms and thus allowed comparison of ISR. All five studies were included in the pooled evidence assessment on any ISR. Only one study provided comparable data on systemic reactions. This study was also included in the pooled evidence assessment on systemic reactions.", "3. Recommendations for diagnosis of TB infection 133 \u2022 C-TST: all five studies were conducted in China and included only HIV-negative adults. All of them included non-random allocation of C-TST versus the TST into two arms; thus, no study evaluating C-TST was included in the pooled evidence assessment on any ISR. Also, no studies including any comparable data on systemic reactions were available. \u2022 Diaskintest: cross-sectional studies using routinely collected data mostly in the Russian Federation, and one in Ukraine, including various populations (adults, children and adolescents \u2013 healthy, contacts of TB patients and with TB). Two studies on Diaskintest provided comparable data on ISR; however, one of them provided no information about the number of participants who experienced any ISR; thus, only one study on Diaskintest was included in the meta-analysis. Fig. 3.1.1.10 Any injection site reactions Proportion of PLHIV: Aggerbeck 2018 ( 7) (25%), Aggerbeck 2019 ( 8) (20%); Hoff 2016 ( 10) (39.5%). Other studies included HIV-negative individuals. Aggerbeck 2018 (7) included children aged under 5 years (20%) and aged 5\u201317 years (31%); Ruhwald 2017 ( 9) included children aged under 5 years (3.5%) and aged 5\u201317 years (8.8%). Other studies included adults. Hoff 2016 (10), Aggerbeck 2019 (8) and Streltsova 2011 (11) included people with TB only. The pooled risk of any ISR due to Cy-Tb (n=2878, 5 studies) and Diaskintest (n=53, 1 study) presented in Fig. 3.1.1.10 was not significantly different from the TST (risk ratio [RR] 1.09; 95% CI: 0.74\u20131.61). The risk of any systemic reaction was only analysable in one study (Cy-Tb) that allowed such comparison, and was not significantly different from the TST (RR 0.84; 95% CI: 0.60\u20131.10). The Diaskintest study was considered to have high risk of bias, while the overall certainty of evidence from the randomized controlled trials for any ISR was judged as high. For any systemic reactions, overall certainty of evidence was judged to be moderate because of the small sample size and wide CI. Following the request from GDG members for the post-marketing surveillance data for Diaskintest, the following data were reported by the manufacturer: in 2019\u20132021, over a 55.7 mln Diaskintest tests were done, with 27 serious adverse effects and 30 non-serious adverse effects. Based on the totality of data, the GDG rated the certainty of evidence as high.", "WHO consolidated guidelines on tuberculosis: Fourth edition 134 Based on the data presented at the GDG meeting, it was concluded that the safety profile of novel TBSTs is similar to that of the TST, and is associated with mostly mild ISR such as itching and pain. From the reviewed studies, there appears to be no safety signal that might affect the choice between specific TBSTs and the TST. However, the group also noted that this was not a full safety review covering product safety, animal or preclinical studies. Regulatory assessment for safety is needed before any of the TBST products are implemented. Cost and cost\u2013effectiveness analysis Two reviews following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were carried out to look at costs and cost\u2013effectiveness of: \u2022 novel TBST, such as Diaskintest, C-TST and Cy-Tb (primary review); and \u2022 TST and IGRA tests (secondary review). The articles searched were those presenting economic evaluations of the diagnostic tests (costs and cost\u2013effectiveness) using a health provider perspective and related to TB infection in humans. The articles reviewed were those written in English, Chinese or Russian languages, and published in Medline, OVID, Chinese Biomedical Literature, China National Knowledge Infrastructure and Russian e-library databases. Quality of studies was assessed using Drummond\u2019s checklist. In addition, a Markov-chain model was developed for the purposes of the GDG meeting, to study the cost\u2013effectiveness of TBSTs versus the currently available tests, the TST and IGRAs. When simulating a cohort of individuals transitioning among different states and steps along the TB cascade of care, the model took into consideration the following parameters: \u2022 prevalence of TB infection in TB-negative individuals, percentage; \u2022 people completing treatment after initiation following a positive TB infection result, percentage; \u2022 people not initiating treatment after testing positive for TB infection, percentage; \u2022 people interrupting treatment after initiation following a positive TB infection test result, percentage; \u2022 progression from TB infection to active TB, probability; \u2022 efficacy of TB infection treatment; \u2022 active TB treatment coverage; \u2022 recovery from active TB (treated + untreated); \u2022 death from active TB (treated + untreated); \u2022 probability of a true positive test result if the patient has TB infection (sensitivity); and \u2022 probability of a true negative test result if the patient does not have TB infection (specificity). Model parameters, unit costs and estimates of diagnostic test accuracy were sourced from the literature, including from", "the systematic reviews mentioned above. The manufacturers of novel TBSTs were also contacted to source costs of the new tests. However, only Generium, the manufacturer of Diaskintest, provided estimated test costs, including delivery costs, for different delivery volumes. Consequently, the modelling study focused on Diaskintest as the representative of the TBST class of tests. The model was parameterized to three countries: Brazil, South Africa and the United Kingdom. Three testing strategies were considered in this analysis: Diaskintest (index); the TST; and", "3. Recommendations for diagnosis of TB infection 135 QuantiFERON-TB IGRAs, either Gold In-Tube or Gold Plus (comparator tests). Outcomes reported included unit cost (in US dollars)5 per patient, incremental cost\u2013effectiveness ratio (ICER) and incremental net benefit per quality-adjusted life year (QALY) gained. Unit costs considered in each country included test kit, staff time, laboratory and disposable costs. Costs were considered from a health system perspective and did not reflect patient or societal costs. Given that only information on Diaskintest was available, a univariate sensitivity analysis on TBST unit costs and a comparison of the results of the three strategies was performed to identify possible maximum unit costs of new TBSTs, for the strategy to remain cost saving or cost- effective, but without specifying a particular type of TBST. The conclusions were based on the predefined research questions outlined below. How large are the resource requirements (costs)? In the eight studies that assessed Diaskintest, most estimated a cost of $1.60 per test. One study evaluated the unit costs considering staff time, consumables and laboratory costs, resulting in a cost of $5.07. This study, using the same costing factors, also estimated the unit cost of C-TST as $9.96. The 29 studies on IGRAs or the TST (or both) estimated an average cost of $37.84 for the TST and $89.33 for IGRAs (accounting for different ingredients). The cost\u2013effectiveness of the tests varied among and within risk groups, with no clear economic consensus around the cost\u2013effectiveness of comparison tests. What is the certainty of the evidence of resource requirements (costs)? Based on Drummond\u2019s scores, the quality of studies that have assessed cost\u2013effectiveness of C-TST and Diaskintest in this review was concerning; only one out of eight studies was of high quality. However, the quality of the studies that assessed cost\u2013effectiveness of the TST and IGRAs was generally high. Does the cost\u2013effectiveness of the intervention favour the intervention or the comparison? Based on the systematic review results, there was insufficient evidence regarding both the cost and cost\u2013effectiveness of novel TBSTs. The quality of the studies was concerning according to the Drummond\u2019s checklist for economic evaluations. More high-quality studies are needed that consider different health settings and risk populations to estimate the cost\u2013effectiveness and the likely economic impact of these tests. Results of the Markov-chain model conducted for the purposes of the GDG meeting concluded that, in Brazil, Diaskintest is cost saving compared with the TST", "and IGRAs. Compared with the TST, Diaskintest is cost saving at $5.60, with an incremental gain of 0.02 QALYs per patient. Compared with IGRAs, Diaskintest is cost saving at $8.40, with an incremental gain of 0.01 QALYs. In South Africa, Diaskintest is more cost saving than the TST or IGRAs. Compared with the TST, Diaskintest is cost saving at $4.39, with an incremental gain of 0.02 QALYs, and compared with IGRAs, it is cost saving at $64.41, with an incremental gain of 0.01 QALYs. In the United Kingdom, Diaskintest is cost saving compared with the TST but not with IGRAs. Compared with the TST, Diaskintest is cost saving at $73.33, with an incremental gain of 0.04 QALYs; however, compared with IGRAs, Diaskintest showed an increase in cost of $15.80 but still an incremental gain of 0.03 QALYs.", "WHO consolidated guidelines on tuberculosis: Fourth edition 136 In summary, the modelling and univariate sensitivity analysis results show that, in Brazil and South Africa, use of Diaskintest would potentially save costs per patient and result in greater health gains (QALYs per patient) compared with the TST and IGRAs. In the United Kingdom, Diaskintest results in health gains but is more expensive in terms of expected cost per patient than IGRAs. Our results also show that, in Brazil and South Africa, IGRAs are more costly to implement than the TST but would result in health gains. However, in the United Kingdom, IGRAs are cheaper to implement and are more cost-effective than the TST. User perspective User perspectives on the value, feasibility, usability and acceptability of diagnostic technologies are important in the implementation of such technologies. If the perspectives of laboratory personnel, clinicians, patients and TB programme personnel are not considered, the technologies risk being inaccessible to and underused by those for whom they are intended. To address questions related to user perspective, the following activities were undertaken: \u2022 Two systematic reviews, which synthesized the qualitative research evidence on end-user values and preferences for the use of specific TBSTs for TB infection, compared with existing tests (IGRAs and the TST). Study quality and confidence in the evidence were evaluated in accordance with the GRADE-CERQual. \u2022 Twenty semi-structured interviews with a diverse range of clinicians, laboratory staff, programme officers and individuals living with TB infection (referred to as \u201cconsumers\u201d throughout this report). \u2022 A discrete choice experiment (DCE) survey, drawing from themes derived in systematic reviews and semi-structured interviews. DCE methodology was used to elicit stated values and preferences from participants (end-users) without directly asking them to state their preferred options. Four studies were identified that met the inclusion criteria for both systematic reviews. From the review on specific TBST, only one data source was identified (from the Russian Federation), and that came from a WHO public call for data relating to the feasibility and acceptability of TBSTs. Participants were parents of children and adolescents with TB infection. From the review on current IGRAs and the TST, three peer-reviewed articles were found to meet the inclusion criteria; these three papers were from the Netherlands, South Africa and the United States of America (USA). Participants included a range of health professionals involved in TB care (Netherlands, South Africa and USA) and PLHIV (South Africa).", "The overall confidence in the quality of the evidence from the studies was low to moderate based on the GRADE-CERQual assessments, because the data lacked richness, with most studies reporting only summaries of participant quotes or limited direct quotes. All studies were conducted on specific subgroups (e.g. PLHIV, or parents of children and adolescents with TB infection). For user interviews, 20 participants were recruited \u2013 13 were TB health care providers (8 from low- and middle-income countries [LMIC]) and seven were people affected by TB (3 from LMIC). Health care providers included programme executives and decision-makers, public health practitioners and advocates, physicians, researchers and laboratory technicians, and a nurse.", "3. Recommendations for diagnosis of TB infection 137 For DCE, a total of 234 participants completed this activity (186 providers and 48 consumers). Overall, 59% of respondents were female and 56% were aged 36\u201355 years; the main countries in which respondents were based were India (26%), the USA (16%), South Africa (9%), Pakistan (8%) and Zimbabwe (7%). The conclusions were based on the predefined research questions outlined below. Is there important uncertainty about or variability in how much end-users value the main outcomes? Qualitative data from the systematic reviews and end-user interviews, and quantitative data from the DCE indicated that health care consumers and providers had similar values and preferences in terms of TB infection tests. Key end-user values included test accuracy, convenience, positive patient experience, cost and resource requirements. In particular, end-users valued tests with high accuracy such as TBST and IGRAs (i.e. low false positive and false negative rates), because they reduce the risk of downstream consequences associated with false positive and false negative results (e.g. anxiety, and the need for additional testing or unnecessary treatment). End-users also preferred having a test that was convenient to administer and access. This included valuing tests that can be accessed in a community or primary care setting, that do not require follow-up visits to read test results, and that can be administered without the need for additional systems or infrastructure to be developed. These findings were initially identified from themes emerging from the systematic reviews and end-user interviews, and were confirmed by the DCE findings. From the qualitative data from the reviews and interviews, all TB infection test options were found to have strengths and limitations in terms of convenience. End-users valued a positive consumer experience. This meant that tests with fewer psychological effects (e.g. anxiety, stigma and stress) and physical consequences (e.g. discomfort) were preferred. Tests that were more accurate tended to be associated with better consumer experience, although some aspects of consumer experience were worse in skin tests (e.g. stigma from the welt and discomfort) compared with non-skin-based tests. Low-cost tests were generally preferred due to greater accessibility in resource-limited contexts (e.g. TBST and the TST). Tests with lower resource requirements were preferred in resource-limited settings (e.g. TBST and the TST); however, this appeared to be less of a consideration in high-income countries. End-users showed a preference towards TB infection tests that used existing infrastructure in their health care", "setting. Data from the DCE confirmed that not requiring an in-person follow-up appointment and not requiring specialist staff or equipment to interpret or administer the test were important end- user preferences for TB testing. What would be the impact on health equity? Qualitative evidence from reviews and end-user interviews indicates that specific TBSTs are unlikely to create any new equity issues. Rather, TBSTs are likely to improve health equity through the provision of a more accurate, low-cost test for resource-limited settings where the TST is already in use. Moreover, their portability and low cost make them suited to use in large-scale screening programmes in vulnerable, hard-to-reach communities. However, it is possible that TBSTs may not affect health equity in low-resource settings that do not already use the TST, because there are barriers to accessing skin and other health care tests in these", "WHO consolidated guidelines on tuberculosis: Fourth edition 138 settings, which would need to be addressed first, regardless of the type of TB test available. In terms of test accessibility, the data from the DCE found that consumers had a strong preference for testing in the community and primary care settings, compared with hospital locations; this finding could have health equity implications. Is the intervention acceptable to key stakeholders? Qualitative data from systematic reviews and end-user interviews suggest that TBSTs were perceived to have greater specificity and sensitivity than the TST. Having greater test accuracy was deemed desirable to avoid the negative consequences of false positives or negatives. However, TBSTs were expected to have many of the same limitations as skin tests in terms of patient experience (e.g. the need for a return visit, discomfort, a welt on the arm and stigma) compared with IGRAs. IGRAs were deemed the preferred test option in countries that already have IGRAs in use, because the required supporting infrastructure is already in place, and because TBSTs would have comparable accuracy and performance, thus would not add value. There were also broader concerns about skin tests because these tests were viewed as a dated, basic technology that is subject to human error and interpretation. Suggestions for improving the acceptability of TBSTs included careful communication during the implementation of this test, with endorsement by health care providers and organizations (e.g. WHO). Data from the DCE found strong and consistent preferences among both health care providers and consumers for tests that minimize false positive and false negative results. The DCE also found that consumers had a strong preference for testing in the community and primary care settings compared with hospital locations. Is the intervention feasible to implement? Findings from the qualitative evidence synthesis (reviews and end-user interviews) support the feasibility of use of TBSTs, but only in settings where the TST is already in use, and the required resourcing and training is already in place. TBST are likely to be low-cost, portable tests that can be well-suited for low-resource health care settings, which may not be able to support IGRAs owing to the greater cost and resources required to implement IGRAs. However, if health care settings already have the necessary infrastructure in place to implement IGRAs, then that is a more feasible test option than any skin tests because IGRAs do not require a return visit to read", "the result (a step where patients may be lost to follow-up). Results from the DCE found that not requiring an in-person follow-up appointment, or specialist staff or equipment to interpret or administer the test, were important preferences for TB testing that would influence feasibility. There was some suggestion that providers preferred more expensive tests (when offered a choice based on a hypothetical cost of $50 compared with $25), although test cost was the least important determinant of test choice. Implementation considerations Considerations for implementation were as follows: \u2022 regulatory approval from national regulatory authorities or other relevant bodies is required before implementation of in vivo diagnostic tests; \u2022 appropriate communication on the new class of tests is necessary, highlighting the difference between the TST and TBSTs; \u2022 implementation of TBSTs requires a cold chain;", "3. Recommendations for diagnosis of TB infection 139 \u2022 well-trained skilled staff are needed to administer and interpret this class of tests; \u2022 multiuse vials will require effective operational planning and batching; hence, single-use vials or vials with fewer doses to match daily needs are preferred; \u2022 procurement and stock management aspects will have to be considered, as with implementing any new class of tests; \u2022 because the reading of the TBST results requires a second patient visit, linkage to care requires reinforcement, to decrease loss to follow-up; \u2022 global market availability and necessary volumes of the new class of tests must be considered; and \u2022 measurement of the TBST reaction size and interpretation must be standardized. Monitoring and evaluation Factors that will require monitoring and evaluation are as follows: \u2022 adverse event monitoring is a gap with the current TST use; thus, recording and reporting systems for results and adverse events need to be introduced when implementing the new tests; and \u2022 there is a need to monitor the linkage between results of the new class of the tests and number of people placed on TPT. Research priorities Research priorities are as follows: \u2022 specificity of Diaskintest and C-TST in populations with a low prevalence of TB infection, and direct head-to-head comparisons of all three TBST; \u2022 assessing the barriers for implementation and patient access; \u2022 additional accuracy studies on high-risk groups: children aged under 5 years, children (aged 5\u201310 years) and adolescents (aged 10\u201318 years), PLHIV, prisoners and migrants; \u2022 studies evaluating the epidemiologic and economic impact of TBST use in the TB infection diagnosis and TPT cascade; \u2022 longitudinal studies to assess the predictive value for active TB compared with current tests; \u2022 economic studies (e.g. cost and cost\u2013effectiveness of TBSTs under different scenarios); and \u2022 studies evaluating the use of digital tools for reading of results, to avoid return patient visits. 3.2. TB skin tests and interferon gamma release assays for the diagnosis of TB infection Testing for TB infection increases the certainty that individuals targeted for treatment will benefit from it. However, there is no gold-standard test to diagnose TB infection. Both currently available tests \u2013 the TST and IGRAs \u2013 are indirect and require a competent immune response to identify people infected with TB. A positive test result by either method is not by itself a reliable indicator of the risk of progression to", "WHO consolidated guidelines on tuberculosis: Fourth edition 140 Recommendation 19. Either a tuberculin skin test (TST) or interferon-gamma release assays (IGRAs) can be used to test for TB infection. (Strong recommendation, very low certainty of the evidence) Justification A systematic review has informed the comparison of the predictive performance of IGRAs and the TST for identifying incident active TB in countries with a TB incidence of more than 100 per 100 000 population (12). Only studies in which the TST was compared with IGRAs in the same population (i.e. \u201chead-to-head\u201d studies) were included. Relative risk ratios for TB for people who tested positive and those who tested negative with the TST and IGRAs were estimated. Five prospective cohort studies were identified, with a total of 7769 participants. The pooled risk ratio estimate for the TST was 1.49 (95% CI: 0.79\u20132.80), and for IGRAs was 2.03 (95% CI: 1.18\u20133.50). Although the estimate for IGRAs was slightly higher than that for the TST, the 95% CIs for the estimates for the TST and IGRAs overlapped and were imprecise. The GDG concluded that the comparison of the TST and IGRAs in the same population does not provide strong evidence that one test should be preferred over the other for predicting progression to active TB disease. The TST may require significantly fewer resources than IGRAs and may be more familiar to practitioners in resource-limited settings; however, recurrent global shortages and stock-outs of the TST reduce prospects for the scale-up of this test and for the programmatic management of TPT. The GDG also noted that equity and access could affect the choice and type of test used. The preferences of people to be tested and programmes depend on several factors, such as the requirement for an adequately equipped laboratory (e.g. for IGRAs) and possible additional costs for people being tested (e.g. for travel) and programmes (e.g. for infrastructure and testing). The GDG strongly recommended the two tests as equivalent options, with relatively similar advantages and disadvantages. The GDG stressed that the global shortage of the TST should be addressed urgently, and called for more investment into research on novel tests for TB infection with better predictive value. The GDG cautioned that imperfect performance of these tests can lead to false negative results, particularly in young children and immunocompromised individuals such as PLHIV with low CD4 counts. The GDG noted the importance of the tests to", "identify recent conversion from negative to positive, particularly among contacts of people with pulmonary TB, which is good practice when initiating TPT. Nevertheless, recent studies among health care workers in the USA tested serially for TB infection showed that conversions from negative to positive and reversions from positive to negative are more commonly identified with IGRAs than with the TST (13). Thus, clinical judgement must still be used to interpret the results of serial TB infection tests. The evidence reviewed and the recommendations given apply only to the use of the two commercially available IGRAs (QuantiFERON-TB Gold In-Tube and T-Spot.", "3. Recommendations for diagnosis of TB infection 141 Evidence base PICO question Could IGRA be used as an alternative to the TST, to identify individuals most at risk of progression from TB infection to active TB in high TB incidence settings? Evidence on intervention effect Five prospective cohort studies were identified, with a total of 7769 participants; four of the studies were newly identified. Three of the studies were conducted in South Africa and two in India (14\u201318). The studies included PLHIV, pregnant women, adolescents, health care workers and household contacts. The pooled risk ratio estimate for the TST was 1.49 (95% CI: 0.79\u2013 2.80), and for IGRAs was 2.03 (95% CI: 1.18\u20133.50). Although the estimate for IGRAs was slightly higher than that for the TST, the 95% CIs for the estimates for the TST and IGRAs overlapped and were imprecise. Furthermore, there was limited evidence for the predictive utility of the tests in specific at-risk populations. Cost\u2013effectiveness IGRA testing is more costly than the TST and requires appropriate laboratory services. TST testing is less costly and can be performed in the field, but it requires a cold chain, two health care visits and training in intradermal injection, reading and interpretation. The incremental cost\u2013effectiveness of IGRAs and the TST appears to be influenced mainly by their accuracy. User perspective The preferences of people to be tested and programmes depend on several factors, such as the requirement for an adequately equipped laboratory (e.g. for IGRAs) and possible additional costs for people being tested (e.g. for travel) and programmes (e.g. for infrastructure and testing). Implementation considerations Where it is feasible, TB infection testing is desirable to identify individuals at highest risk for developing active TB. However, it is not required in PLHIV or in household contacts aged under 5 years. In HIV-negative household contacts aged 5 years and older, and in other risk groups, TB infection tests are recommended, but their unavailability should not be a barrier to treating people who are judged to be at higher risk. The GDG noted that the availability and affordability of the tests could determine which TB infection test is used. Other considerations include the structure of the health system, feasibility of implementation and infrastructure requirements. Operational difficulties should be considered in deciding which test to use. For example, IGRAs requires phlebotomy, which can be difficult, particularly in young children; they also require laboratory infrastructure, technical", "expertise and expensive equipment, and their sensitivity is reduced in children aged under 2 years and PLHIV. However, only a single visit is required to do an IGRA test (although patients may have to make a second visit to receive the result). The TST requires a cold chain, two health care visits and training in intradermal injection, reading and interpretation. One other practical advantage of IGRAs over the TST is that IGRAs are notsusceptible to a \u201cbooster response\u201d, which makes a two-step approach necessary for the TST in situations where reactivity to the TST has waned since infection.", "WHO consolidated guidelines on tuberculosis: Fourth edition 142 BCG vaccination plays a decisive role in reducing the specificity of the TST, although the GDG noted that the impact of BCG vaccination on the specificity of the TST depends on the strain of vaccine used, the age at which the vaccine is given and the number of doses administered. When BCG is given at birth, as is the case in most parts of the world, it has a variable, limited impact on TST specificity (19). The GDG agreed that a history of BCG vaccination has a limited effect on interpretation of TST results later in life; hence, BCG vaccination should not be a determining factor in selecting a test. Neither the TST nor IGRAs are to be used to diagnose active TB disease; also, they are not to be used for diagnostic work-up of adults suspected of having active TB. Research priorities There is a critical need for diagnostic tests with improved performance and predictive value for progression to active TB. In addition, the performance of TB infection tests should be evaluated in various risk groups, to assess reinfection and to understand how best to use available tools in each population (e.g. in combination, or sequential use of the TST and IGRAs). Data synthesis was structured around the preset PICO question, as outlined above. See Web Annex H for additional information on evidence synthesis and analysis. 3.3. TB skin tests and interferon gamma release assays for the diagnosis of TB disease Recommendation 20. Interferon-gamma release assays (IGRAs) (and the tuberculin skin test [TST]) should not be used in low- and middle-income countries for the diagnosis of pulmonary or extrapulmonary TB, or for the diagnostic work-up of adults (including people living with HIV) suspected of active TB in these settings (strong recommendation) The Guideline Development Group concluded that both the sensitivity and specificity of IGRAs in detecting active TB among individuals presumed of having TB were suboptimal and the quality of evidence was low. They also recommended that these tests not be used as a replacement for conventional microbiological diagnosis of pulmonary and extrapulmonary TB. The Guideline Development Group noted that current evidence did not support the use of IGRAs or the TST as part of the diagnostic work-up of adults presumed of active TB, irrespective of HIV status. This recommendation placed a high value on avoiding the consequences of unnecessary treatment", "3. Recommendations for diagnosis of TB infection 143 Evidence base A systematic, structured, evidence-based process for TB diagnostic policy generation was followed. The first step constituted systematic reviews and meta-analysis of available data (published and unpublished), using standard methods appropriate for diagnostic accuracy studies. The second step involved the convening of a GDG to evaluate the strength of the evidence base, evaluate the risks and benefits of using IGRAs in LMIC and identify gaps to be addressed in future research. Based on the Expert Group findings, the third and final step involved development of a WHO policy guidance, with eventual dissemination to WHO Member States for implementation. The GRADE system, adopted by WHO for all policy and guideline development, was used by the GDG. Given the absence of studies evaluating patient-important outcomes among TB suspects randomized to treatment based on IGRA results, reviews were focused on the diagnostic accuracy of IGRAs versus the TST in detecting TB infection or TB disease. Recognizing that test results may be surrogates for patient-important outcomes, the GDG evaluated the accuracy of IGRAs while also drawing inferences on the likely impact of these tests on patient outcomes, as reflected by false negatives (i.e. cases of TB infection missed) or false positives. Systematic reviews were undertaken following detailed protocols with predefined questions relevant to the individual topics. Summaries of methodologies followed for each topic are given in the relevant sections below. PICO questions What is the diagnostic accuracy of commercial IGRAs for pulmonary TB in adult pulmonary TB suspects and confirmed TB cases in LMIC as compared with microbiological (culture or smear- microscopy) or clinical diagnosis of pulmonary TB? Hierarchy of reference standards Studies evaluating the performance of IGRAs are hampered by the lack of a gold standard to distinguish the presence or absence of TB infection. Since diagnostic accuracy for TB infection could not be directly assessed, a hierarchy of reference standards was developed and agreed beforehand with the systematic reviewers, to evaluate the role of IGRAs, depending on the individual topic (i.e. not all systematic reviews necessarily used the hierarchy). Primary outcomes were predefined for each systematic review as relevant; for example, the predictive value of IGRAs for development of active TB, the sensitivity of IGRAs in individuals with culture- confirmed active TB (as a surrogate reference standard for TB infection), and the correlation between IGRA and TST results. In addition to primary outcomes,", "specific characteristics of IGRAs that could influence their overall utility were evaluated where relevant; for example, the proportion of indeterminate IGRA results (i.e. not able to be interpreted, either due to a high IFN-\u03b3 response in the negative control or a low IFN-\u03b3 response in the positive control), the impact of HIV-related immunosuppression (i.e. CD4+ cell count) on test performance where available and correlation of IGRA results with an exposure gradient (typically used in contact and outbreak investigations).", "WHO consolidated guidelines on tuberculosis: Fourth edition 144 Studies search, selection and quality assessment All studies evaluating IGRAs published up to the end of May 2010 were reviewed using predefined data search strings. In addition to database searches, bibliographies of reviews and guidelines were reviewed, citations of all included studies were screened, and experts in the field as well as IGRA manufacturers were contacted to identify additional studies (published, unpublished and ongoing). Pertinent information not reported in the original publications was requested from the primary authors of all studies included by the systematic reviewers. Studies that evaluated the performance of currently available commercial IGRAs, published in all languages and in all LMIC, were reviewed by individual topic. Only studies evaluating IGRA performance in LMIC were included in this analysis. Excluded were studies that evaluated non- commercial (i.e. in-house) IGRAs, older generation IGRAs (i.e. PPD-based IGRAs) and IGRAs performed in specimens other than blood; studies that were focused on the effect of anti-TB treatment on the IGRA response; studies including fewer than 10 individuals; studies reporting insufficient data to determine diagnostic accuracy measures; and conference abstracts and letters without original data, and reviews. Study quality was assessed by relevant standardized methods, depending on the topic. For primary outcomes focused on test accuracy, quality was appraised using a subset of relevant criteria from QUADAS, a validated tool for diagnostic accuracy studies. For studies of the predictive value of IGRAs, quality was appraised with a modified version of the Newcastle- Ottawa Scale (NOS) for longitudinal or cohort studies. Conflicts of interest are a known concern in TB diagnostic studies; therefore, the systematic reviews added a quality item about involvement of commercial test manufacturers in published studies; they also reported whether IGRA manufacturers had any involvement with the design or conduct of each study, including donation of test materials, provision of monetary support, work or financial relationships with study authors, and participation in data analysis. Data synthesis and meta-analysis A standardized overall approach was specified a priori for each systematic review, to account for significant heterogeneity in results expected between studies. First, data were synthesized separately for each commercial IGRA and by the World Bank country income classification (LMIC versus high-income countries) as a surrogate for TB incidence. Second, heterogeneity was visually assessed using forest plots, and the variation in study results attributable to heterogeneity was characterized (I-squared statistic) and statistically tested (chi-squared test).", "Third, pooled estimates were calculated using random-effects modelling, which provides more conservative estimates than fixed-effects modelling when heterogeneity is present. For each individual study, all outcomes for which data were available were assessed. First, forest plots were generated to display the individual study estimates and their 95% CIs. Pooled estimates were calculated when at least three studies were available in any subgroup, and individual study results were summarized when fewer than four studies were available. Standard statistical packages were used for analyses.", "3. Recommendations for diagnosis of TB infection 145 Use of IGRAs in the diagnosis of active TB Studies included were those that evaluated the performance of the technologies of interest for the diagnosis of TB disease among adult (>15 years) with presumed TB or people with TB in LMIC. The initial search yielded 789 citations. After full-text review of 185 papers evaluating IGRAs for the diagnosis of active TB, 22 were determined to meet eligibility criteria, covering 33 unique evaluations of one or more IGRAs (hereafter referred to as studies) in 19 published and three unpublished reports. Of the 33 studies, 10 (30%) were from low-income countries and 23 (70%) were from middle-income countries. Seventeen studies (52%) included PLHIV (n=1057), and 27 studies (82%) involved ambulatory subjects (outpatients as well as hospitalized patients. IGRAs were performed in people suspected of having active TB in 19 studies (58%) and in people with known active TB in 14 studies (42%). Because of the focus on diagnostic accuracy for active TB and the high prevalence of TB infection in high TB burden settings, IGRA specificity was estimated exclusively among studies enrolling TB suspects where the diagnostic work-up ultimately showed no evidence of active disease. The results demonstrated the following in LMIC: \u2022 The sensitivity of IGRAs in detecting active TB among people suspected of having TB ranged from 73% to 83% and specificity from 49% to 58%. Therefore, one in four patients, on average, with culture-confirmed active TB could be expected to be IGRA-negative in LMIC, with serious consequences for patients in terms of morbidity and mortality. \u2022 There was no evidence that IGRAs have added value beyond conventional microbiological tests for the diagnosis of active TB. Among studies that enrolled TB suspects (i.e. patients with diagnostic uncertainty), both IGRAs demonstrated suboptimal \u201crule-out\u201d values for TB disease. \u2022 Even though data were limited, the sensitivity of both IGRAs was lower among PLHIV (about 60\u201370%), suggesting that nearly one in three PLHIV with active TB would be IGRA-negative. \u2022 There was no consistent evidence that either of the two IGRAs was more sensitive than the TST for active TB diagnosis, although comparisons with pooled estimates of TST sensitivity were difficult to interpret owing to substantial heterogeneity. \u2022 The few available head-to-head comparisons between QFT-GIT and T-Spot demonstrated higher sensitivity for the T-Spot platform, although this difference did not reach statistical significance. \u2022 The specificity", "of both IGRAs for active TB was low, regardless of HIV status, and results suggested that one in two patients without active TB would be IGRA-positive, with adverse consequences for patients because of unnecessary therapy for TB and a missed differential diagnosis. \u2022 Two unpublished reports reported no incremental or added value of IGRA test results combined with important baseline patient characteristics (e.g. demographics, symptoms or chest radiograph findings). Thus, these reports did not support a meaningful contribution of IGRAs for the diagnosis of active TB beyond readily available patient data and conventional tests.", "WHO consolidated guidelines on tuberculosis: Fourth edition 146 \u2022 The systematic review focused on the use of IGRAs to diagnose active pulmonary TB, given that data for extrapulmonary TB were lacking; nevertheless, the GDG consensus was that recommendations for pulmonary TB could reasonably be extrapolated to extrapulmonary TB. \u2022 Industry involvement was unknown in 18% of studies and acknowledged in 27% of studies, including donation of IGRA kits as well as work or financial relationships between authors and IGRA manufacturers. Strengths and limitations of the evidence base Strengths and limitations were as follows: \u2022 Heterogeneity was substantial for the primary outcomes of sensitivity and specificity. Activities performed to minimize heterogeneity were empirical random-effects weighting, excluding studies contributing fewer than 10 eligible individuals, and separately synthesizing data for currently manufactured IGRAs. \u2022 No standard criteria exist for defining high TB incidence countries, and the World Bank income classification is an imperfect surrogate for national TB incidence; nevertheless, results were fundamentally unchanged when restricted to countries with an arbitrarily chosen annual TB incidence of at least 50 per 100 000 population. \u2022 It is possible that ongoing studies were missed, despite systematic searching. It is also possible that studies that found poor IGRA performance were less likely to be published. Given the lack of statistical methods to account for publication bias in diagnostic meta- analyses, it would be prudent to assume some degree of overestimation of estimates due to publication bias. \u2022 The systematic review focused on test accuracy (i.e. sensitivity and specificity) and indirect assessment of patient impact (false positive and false negative results). None of the studies reviewed provided information on patient-important outcomes (i.e. showing that IGRAs used in a given situation resulted in a clinically relevant improvement in patient care or outcomes). In addition, no information was available on the values and preferences of patients. Data synthesis was structured around the preset PICO question, as outlined above. Web Annex I provides additional information on evidence synthesis and analysis. Operational aspects of the use of IGRAs Operational aspects of the use of IGRAs were as follows: \u2022 Cost of IGRAs was mentioned by four studies, which all stated that the assays are too expensive and that this is a limitation to their use. \u2022 Only one study addressed reproducibility of T-Spot by assessing inter-observer agreement; it showed excellent correlation. No other study mentioned the issue of test reproducibility. \u2022 Twelve", "studies reported on accepted transport times of samples to the laboratory, which were mainly less than 6 hours (i.e. within the limit accepted by the test manufacturers). One study accepted a transport time of 16 hours and another 24 hours. None reported on the impact of the transport times (i.e. delay between drawing the blood and initiating the IGRA test) and IGRA test results or performance. \u2022 No study reported on time-to-result for IGRAs.", "3. Recommendations for diagnosis of TB infection 147 \u2022 Four studies reported on the impact of IGRAs on TB therapy. In two studies, IGRA results were reported to clinicians; one study did not discuss the consequences, and in the other study QFT-positive children and adolescents received preventive chemotherapy. The other two studies commented on the reduced number of patients that would require preventive therapy if IGRAs were part of the diagnostic algorithm. \u2022 The following aspects related to the feasibility of IGRAs were highlighted: \u2013 blood amounts required may be an issue; however, tests were performed with less than 2 mL of blood (T-Spot) in some studies; \u2013 a strong interferon response in negative control tubes (high background results) in QFT may reflect the influence of other coincident diseases; \u2013 standardization and generation of automated, quantitative results should render IGRAs more objective than the TST; and \u2013 a well-equipped laboratory, expensive equipment and training are required for IGRA test performance, which may cause logistical problems. Research priorities Targeted further research to identify IGRAs with improved accuracy is strongly encouraged. Such research should be based on adequate study design, including quality principles such as representative suspect populations, prospective follow-up, and adequate and explicit blinding. It is also strongly recommended that proof-of-principle studies be followed by evidence produced from prospectively implemented and well-designed evaluation and demonstration studies, including assessment of patient impact. 3.4. References 1. Public announcement to TB in vitro diagnostics manufacturers, procurement agencies and national TB programmes on inclusion of WHO prequalification for TB in vitro diagnostics. Geneva: World Health Organization; 2021 ( https://extranet.who.int/pqweb/sites/default/files/documents/210211_ PublicAnnouncement_TB_%20in-vitro-diagnostics.pdf). 2. Sch\u00fcnemann HJ, Mustafa RA, Brozek J, Steingart KR, Leeflang M, Murad MH et al. GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables. J Clin Epidemiol. 2020;122:142\u201352 (https://pubmed.ncbi.nlm.nih.gov/32058069/). 3. Sch\u00fcnemann HJ, Mustafa RA, Brozek J, Steingart KR, Leeflang M, Murad MH et al. GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy. J Clin Epidemiol. 2020;122:129\u201341 (https://pubmed.ncbi.nlm.nih.gov/32060007/). 4. McMaster University. GRADEpro GDT [website]. 2020 (https://gradepro.org/). 5. Starshinova A, Zhuravlev V, Dovgaluk I, Panteleev A, Manina V, Zinchenko U et al. A comparison of intradermal test with recombinant tuberculosis allergen (diaskintest) with other immunologic tests in the diagnosis", "of tuberculosis infection. International Journal of Mycobacteriology. 2018;7(1):32. 6. Starshinova A, Zinchenko Y, Istomina E, Basantsova N, Filatov M, Belyaeva E et al. [Diagnosis of latent tuberculosis infection in personnel of various institutions and determination of the risk group for tuberculosis]. Bioprep Prev Diagnosis. Treat. 2019;19:178\u201384. 7. Aggerbeck H, Ruhwald M, Hoff ST, Borregaard B, Hellstrom E, Malahleha M et al. C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV-infected adults: A phase 3 trial. PLoS One. 2018;13(9):e0204554 (https://www.ncbi.nlm.nih.gov/pubmed/30248152).", "WHO consolidated guidelines on tuberculosis: Fourth edition 148 8. Aggerbeck H, Ruhwald M, Hoff S, Tingskov P, Hellstrom E, Malahleha M et al. Interaction between C-Tb and PPD given concomitantly in a split-body randomised controlled trial. Int J Tuberc Lung Dis. 2019;23(1):38\u201344. 9. Ruhwald M, Aggerbeck H, Gallardo RV, Hoff ST, Villate JI, Borregaard B et al. Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon gamma release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med. 2017;5(4):259\u201368 (https://www.ncbi.nlm.nih.gov/pubmed/28159608). 10. Hoff ST, Peter JG, Theron G, Pascoe M, Tingskov PN, Aggerbeck H et al. Sensitivity of C-Tb: a novel RD-1-specific skin test for the diagnosis of tuberculosis infection. Eur Respir J. 2016;47(3):919\u201328 (https://www.ncbi.nlm.nih.gov/pubmed/26677940). 11. Streltsova E, Ryzhkova O, Bespalova A. Comparative clinical studies of skin test Diaskintest and Mantoux test in patients with pulmonary tuberculosis. Astrakhan Medical Journal. 2011;6(1):265\u201370. 12. Rangaka MX, Wilkinson KA, Glynn JR, Ling D, Menzies D, Mwansa-Kambafwile J et al. Predictive value of interferon-y release assays for incident active tuberculosis: a systematic review and meta- analysis. Lancet Infect Dis. 2012;12(1):45\u201355 (https://pubmed.ncbi.nlm.nih.gov/21846592/). 13. Dorman SE, Belknap R, Graviss EA, Reves R, Schluger N, Weinfurter P et al. Interferon-y release assays and tuberculin skin testing for diagnosis of latent tuberculosis infection in healthcare workers in the United States. Am J Respir Crit Care Med. 2014;189(1):77\u201387 ( https://pubmed.ncbi.nlm.nih. gov/24299555/). 14. Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G et al. Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. Lancet. 2014;384(9944):682\u201390 (https://pubmed.ncbi.nlm.nih.gov/24835842/). 15. Mahomed H, Hawkridge T, Verver S, Abrahams D, Geiter L, Hatherill M et al. The tuberculin skin test versus QuantiFERON TB Gold\u00ae in predicting tuberculosis disease in an adolescent cohort study in South Africa. PLoS One. 2011;6(3):e17984 (https://pubmed.ncbi.nlm.nih.gov/21479236/). 16. Mathad JS, Bhosale R, Balasubramanian U, Kanade S, Mave V, Suryavanshi N et al. Quantitative IFN-\u03b3 and IL-2 response associated with latent tuberculosis test discordance in HIV-infected pregnant women. Am J Respir Crit Care Med. 2016;193(12):1421\u20138 (https://pubmed.ncbi.nlm.nih. gov/26765255/). 17. McCarthy KM, Scott LE, Gous N, Tellie M, Venter WD, Stevens WS et al. High incidence of latent tuberculous infection among South African health workers: an urgent call for action. Int J Tuberc Lung Dis. 2015;19(6):647\u201353 (https://pubmed.ncbi.nlm.nih.gov/25946353/). 18. Sharma SK, Vashishtha R, Chauhan LS, Sreenivas V, Seth D. Comparison of TST and IGRA in diagnosis", "149 Annex 1. Guideline development methods Methods used to develop World Health Organization guidelines To develop new or update existing guidelines for methods and tools to diagnose tuberculosis (TB), the World Health Organization (WHO) Global TB Programme commissions systematic reviews on the performance or use of the tool or method in question. A systematic review provides a summary of the current literature on diagnostic accuracy or user aspects, for the diagnosis of TB or the detection of anti-TB drug resistance in adults or children (or both) with signs and symptoms of TB. The certainty of the evidence is assessed consistently for documented evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. GRADE produces an overall quality assessment (or certainty) of evidence and a framework for translating evidence into recommendations. The certainty of the evidence is rated as high, moderate, low or very low. These four categories imply a gradient of confidence in the estimates. Even if a diagnostic accuracy study is of observational design, it would initially be considered high-quality evidence in the GRADE approach (1). In addition, the WHO Global TB Programme commissions systematic reviews to collect evidence in the field of resource use (i.e. cost and cost\u2013effectiveness), as well as end-user perspectives on particular diagnostic tests or interventions. This evidence-to-recommendation process will inform domains such as feasibility, accessibility, equity and end-user values. If systematic review evidence is unavailable or is scarce, the potential subsequent effects can be modelled for both diagnostic accuracy as well as cost and cost\u2013effectiveness. For instance, the prevalence of the disease in question, combined with the sensitivity and specificity of a certain test, can be used to estimate the number of false positives and false negatives in a population. Similarly, data on expenditures and cost\u2013effectiveness ratios can be estimated and modelled, based on economical and epidemiological data. Finally, qualitative evidence on the end-user perspective of using a particular test may be generated through end-user interviews if data are scarce in the public domain. Following a systematic review, the WHO Global TB Programme convenes a Guideline Development Group (GDG) meeting to review the collected evidence. The GDG is made up of external experts whose central task is to develop evidence-based recommendations. The GDG also performs the important task of finalizing the scope and key questions of the guideline in PICO (i.e. population, intervention, comparator and outcomes) format.", "WHO consolidated guidelines on tuberculosis: Fourth edition 150 This group should be established early in the guideline development process, once the Steering Group has defined the guideline\u2019s general scope and target audience, and has begun drafting the key questions. The GDG should be composed of relevant technical experts; end-users, such as programme managers and health professionals, who will adopt, adapt and implement the guideline; representatives of groups most affected by the guideline\u2019s recommendations, such as service users and representatives of disadvantaged groups; experts in assessing evidence and developing guidelines informed by evidence; and other technical experts as required (e.g. a health economist or an expert on equity, human rights and gender). Recommendations are developed based on consensus among GDG members, where possible. When it is not possible to reach consensus, a vote is taken. When a draft guideline is developed by a WHO steering committee, it is reviewed initially by GDG members and subsequently by an External Review Group (ERG). The ERG is made up of individuals interested in the subject, and may include the same categories of specialists as the GDG. When the ERG reviews the final guideline, its role is to identify any errors or missing data, and to comment on clarity, setting, specific issues and implications for implementation \u2013 not to change the recommendations formulated by the GDG (2). Formulation of the recommendations Evidence is synthesized and presented in GRADE evidence tables. The evidence to decision (EtD) framework is used subsequently to facilitate consideration of the evidence and development of recommendations in a structured and transparent manner. Finally, recommendations are developed based on consensus among GDG members where possible. If it is not possible to reach consensus, then voting takes place. Decisions on the direction and strength of the recommendations are also made using the EtD framework. Factors that influenced the direction and strength of a recommendation in this guideline were: \u2022 priority of a problem; \u2022 test accuracy; \u2022 balance between desirable and undesirable effects; \u2022 certainty of: \u2013 evidence of test accuracy; \u2013 evidence on direct benefits and harms from the test; \u2013 management guided by the test results; \u2013 link between test results and management; \u2022 confidence in values and preferences and their variability; \u2022 resource requirements; \u2022 cost\u2013effectiveness; \u2022 equity; \u2022 acceptability; and \u2022 feasibility. These factors are discussed below.", "Annex 1. Guideline development methods 151 Priority of a problem The GDG considers whether the overall consequences of a problem (e.g. increased morbidity, mortality and economic effects) are serious and urgent. The global situation is considered and available data reviewed. In most cases, the problem must be serious and urgent to be considered by a GDG. Test accuracy The pooled sensitivity and specificity presented in the GRADE evidence profile is assessed. Preferably and if available the review includes studies with both microbiological reference standards (culture) as well as composite reference standards (e.g. in children and in patients with extrapulmonary TB). Balance between desirable and undesirable effects Under this component, GDG members are asked to judge the anticipated benefits and harms from the test in question, including direct effects of the test (e.g. benefits such as faster diagnosis, and harms such as adverse effects from administration of the test). In addition, the possible subsequent effects of the test must be included; for instance, effects of treatment after a positive diagnosis (cure or decrease in mortality), and the effect of no treatment or further testing after a negative test result. Evidence, ideally retrieved from systematic reviews of randomized controlled trials (RCTs) of the test, should inform the GDG of these downstream effects. If evidence from RCTs is not available, diagnostic accuracy studies can be used. In the latter, true positive and true negative diagnosed cases are taken as benefits, whereas false positive and false negative cases are taken as harms. Certainty of the evidence Certainty of the evidence of test accuracy is judged scored on a scale from very low, via low and moderate, to high. Certainty of the evidence on direct benefits and harms from the test are assessed and scored in a similar way. Certainty of management For certainty of patient management being guided by the test results, the GDG focuses on whether the management would be any different, should it be guided by the test results. For certainty of the link between test results and management, the panel assesses how quickly and effectively test results can transfer to management decisions. Confidence in values and preferences and their variability The value of the test to improve diagnosis and its impact on patient care is evaluated and scored with the help of evidence from qualitative research. The impact on notification and, moreover, the ability of the test to increase case notification", "WHO consolidated guidelines on tuberculosis: Fourth edition 152 Resource requirements In relation to resource requirements, the following questions are answered: \u2022 How large are the resource requirements for test implementation? \u2022 What is the certainty of the evidence about resource requirements? \u2022 Does the cost\u2013effectiveness of the intervention favour the intervention or the comparison? Cost\u2013effectiveness Available evidence on cost\u2013effectiveness is evaluated and scored. Equity GDG members consider whether implementing the tool or method will positively or negatively affect access to health care (e.g. will it be possible to implement the test in distinct levels of health care or through self-administration, or are there other ways to make the tools or method available to all levels of the health care system). Acceptability In terms of acceptability, the panel considers whether the tool or method will be acceptable by all relevant stakeholders, such as health workers, health managers and patients. Feasibility The GDG considers how feasible it is to implement a tool or method in various settings. Aspects such as training and refresher training needs, hands-on time, biosafety requirements, time to results, service and maintenance, calibration, and effect on diagnostic algorithms are all taken into account in the final score. For more details on the transition from evidence to recommendations, see Web Annex 3 : Evidence to decision tables. Reference for Annex 1 1. Sch\u00fcnemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336:1106\u201310. doi: https://doi.org/10.1136/bmj.39500.677199.AE. 2. Handbook for guideline development 2nd ed. Geneva: World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714).", "153 Annex 2. Conflict of interest assessment for Guideline Development Group and External Review Group members Before being considered for group membership, each Guideline Development Group (GDG) and External Review Group candidate was required to submit a completed declaration of interest (DOI) form. In addition, a preliminary internet search was performed to identify any obvious public controversies or interests that may lead to compromising situations for the World Health Organization (WHO) and the expert concerned. The candidate\u2019s curriculum vitae (CV) and DOI, and information retrieved from the internet, were examined by steering committee members to assess whether there were, or may be, actual or perceived conflicts of interest and, if so, whether a management plan was required. This evaluation process, and resultant management plans, were based on the Guidelines for declaration of interests (WHO experts) (1) and the WHO handbook for guideline development (2nd edition) (2). Both financial and non-financial interests were considered. A \u201csignificant\u201d conflict of interest would include: \u2022 \u201cintellectual bias\u201d, where an individual may have repeatedly and publicly taken a position on an issue under review, which may affect the individual\u2019s objectivity and independence in the global policy development process; \u2022 involvement in research or publication of materials related to issues under review; and \u2022 a financial interest above US$ 5000. Developers of any assay are never involved in the process of policy development; this is automatically considered a conflict of interest. Once a determination was made that either no conflict of interest existed, or any conflict of interest could be appropriately managed, and a decision had been made to appoint the candidate, the name and a brief biography of each candidate were published on the WHO website for at least 14 days before the meeting, for public notice and comment.", "WHO consolidated guidelines on tuberculosis: Fourth edition 154 DOI statements are summarized by the WHO steering committee at the start of the meeting. Selected individuals with intellectual or research involvement were invited as technical resource persons to provide technical input and answer technical questions. These individuals did not participate in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evaluation process and were excluded from the group discussions when recommendations were developed. Table A.2.1. Summary of the declarations of interest statements for the GDG members: \u201cMolecular assays intended as initial tests\u201d, 7\u201318 December 2020 GDG member Interests declared Conclusion Holger Sch\u00fcnemann None declared No conflict of interest Jeremiah Chakaya Muhwa None declared No conflict of interest Denise Arakaki-Sanchez None declared No conflict of interest David Branigan None declared No conflict of interest Daniela Cirillo Evaluation of an XDR test prototype. Project funded by Cepheid and FIND. Budget (Research Unit): US$ 14 296; 2018. Member of the Scientific Advisory Board (BIOMERIEUX). Budget (self): US$ 1000; 2020\u20132021. Evaluation of the blood stability for VIDAS (BIOMERIEUX). Budget (Research Unit): US$ 11 200; 2019. Significant conflict of interest \u2013 excluded from the deliberations on low complexity automated NAATs Celina Anna Maria Garfin None declared No conflict of interest Petra de Haas None declared No conflict of interest Patricia Hall Receives funding from PEPFAR; uses PEPFAR funding to procure TB diagnostics tests and supplies for TB, HIV infant diagnostic and HIV viral load testing across multiple countries. Provides technical input into the PEPFAR Country Operational Guidance, including inputs on the appropriate procurement and use of TB and HIV instrumentation and test types. Oversees a global Cepheid GeneXpert- based proficiency testing program and provides technical assistance to PEPFAR- supported CDC country offices and partner ministries of health on the selection and implementation of TB and HIV diagnostic tests and testing resources. Non-significant conflict of interest Rumina Hasan None declared No conflict of interest", "Annex 2. Conflict of interest assessment for Guideline Development Group and External Review Group members 155 GDG member Interests declared Conclusion Xia Hui None declared No conflict of interest Farzana Ismail Evaluation of an XDR test prototype (Cepheid). Budget (Research Unit): US$ 140 000; 2020. Bedaquiline post- marketing surveillance and emerging resistance (Janssen). Budget (Research Unit): US$ 300 000; ongoing. Latent TB infection in health care workers (Qiagen). Budget (Research Unit): consumables and personnel; ongoing. Sponsorship to the IUATLD conference participation, Den Haag (self); 2018. Significant conflict of interest \u2013 excluded from the deliberations on low complexity automated NAATs Katharina Kranzer EDCTP: total budget about \u20ac3.2 million across 6 institutions; FIND: non-TB-related study (study on antimicrobial resistance), US$ 21 000; Cepheid: non-TB-related study (study on STIs), in-kind contributions of 3000 cartridges and the loan of an Xpert machine; Cepheid: TB-related study about 3 gene signature, in-kind contribution of 3500 cartridges and a loan of an Xpert machine; Roche: consumables for validations study in 2015\u20132016. Significant conflict of interest \u2013 excluded from the deliberations on moderate complexity automated NAATs Blessina Kumar None declared No conflict of interest Nagalineswaran Kumarasamy None declared No conflict of interest Lindiwe Mvusi None declared No conflict of interest Viet Nhung Nguyen None declared No conflict of interest Mark Nicol Research grant funding received by the institution for studies of a broad range of novel diagnostics for TB, including NAATs (among others, BD MAX\u2122, one of the tests of interest for the actual GDG). Gates Foundation; NIH; Wellcome Trust; FIND. Employer (University) received funding. Significant (several million US dollars). Ongoing funding from FIND, NIH; co-shares a pending patent for a novel method to extract and purify DNA from sputum samples (not related to or used by any commercial test for TB). Patent belongs to incumbent. No commercial value at present. Significant conflict of interest \u2013 excluded from the deliberations on moderate complexity automated NAATs", "WHO consolidated guidelines on tuberculosis: Fourth edition 156 GDG member Interests declared Conclusion Leen Rigouts Research support: the research unit received financial support through FIND for the coordination of and participation in a multicentre evaluation of the Genoscholar PZA-LPA. Part of that funding came from Nipro. Non-monetary renumeration: the research unit received the Genoscholar PZA-LPA kits to conduct evaluations of the test (multicentre study via FIND plus additional ongoing evaluation in the unit). Significant conflict of interest \u2013 excluded from the deliberations on high complexity hybridization-based NAATs Thomas Shinnick As an independent consultant, received contracts and travel support from WHO, FIND and USAID for work related to laboratory strengthening and developing global guidance documents; ongoing. Non-significant conflict of interest Hojoon Sohn None declared No conflict of interest Sabira Tahseen None declared No conflict of interest Ezio Tavora dos Santos Filho Has coordinated community advisory boards to the PROVE-IT study (TREAT-TB grant, Union/USAID) in Brazil (REDE-TB) from 2010 to 2015. Currently following up, as an interested party (not as a member of the study team, but as a community advisory board coordinator of other studies), the implementation of the Truenat validation study in Brazil, among other BRICS cooperation studies. Intends to follow up the study, settling establishing system of community advisory boards oversight and protocol analysis in Brazil and other partner countries. Significant conflict of interest perceived for Molbio Truenat evaluation \u2013 excluded from a discussion on Molbio Truenat Carrie Tudor Employment (starting January 2015) in the International Council of Nurses, whose TB project received funding from the Eli Lilly Foundation \u2013 Lilly MDR-TB Partnership. Funding received was approx US$ 1 million from 2013 to 2019. Current funding period for 2019 is approx. US$ 100 000. Non-significant conflict of interest Diana Vakhrusheva None declared No conflict of interest", "Annex 2. Conflict of interest assessment for Guideline Development Group and External Review Group members 157 GDG member Interests declared Conclusion Elisabetta Walters Recipient of grants and a scholarship for doctoral research which included work on GeneXpert MTB/RIF for the diagnosis of intrathoracic TB in children. South African Medical Research Council grant (2012\u2013 2015) and scholarship (2015\u20132018). South African National Research Foundation. FIND. TBTC (CDC); (Research Unit): ZAR 4.2 million; US$ 90 000; 2012\u20132018. Non-significant conflict of interest AIDS: acquired immunodeficiency syndrome; BRICS: Brazil, Russia, India, China and South Africa; CDC: Centers for Disease Control and Prevention; DNA: deoxyribonucleic acid; EDCTP: European and Developing Countries Clinical Trials Partnership; FIND: Foundation for Innovative New Diagnostics; GDG: Guideline Development Group; HIV: human immunodeficiency virus; IUATLD: International Union Against Tuberculosis and Lung Disease; MDR-TB: multidrug-resistant TB; NAAT: nucleic acid amplification test; NIH: National Institutes of Health; PEPFAR: United States President\u2019s Emergency Plan for AIDS Relief; STI: sexually transmitted infection; TB: tuberculosis; TBTC: Tuberculosis Trials Consortium; USAID: United States Agency for International Development; WHO: World Health Organization; XDR: extensively drug-resistant. Table A.2.2. Summary of the declarations of interest statements for the ERG members: \u201cMolecular assays intended as initial tests\u201d, 7\u201318 December 2020 ERG member Interests declared Conclusion Lucilaine Ferrazoli None declared No conflict of interest Alaine Umubyeyi Nyaruhirira None declared No conflict of interest Elisa Tagliani Involved in the WHO Expert Review Panel for Diagnostics Round 15; specifically, in the evaluation of the BD MAX platform; \u20ac5940. A unit at San Raffaele has received funding from an EDCTP grant (TB-CAPT) to FIND. Incumbent has collaborated with FIND in a multicentre clinical study to assess the performance of the Xpert MTB/XDR assay. Non-significant conflict of interest for External reviewer. Management of potential conflict of interest by interpretation of the comments in the context of conflict of interest Francis Varaine None declared No conflict of interest Danila Zimenkov None declared No conflict of interest EDCTP: European and Developing Countries Clinical Trials Partnership; ERG: External Review Group; FIND: Foundation for Innovative New Diagnostics; WHO: World Health Organization.", "WHO consolidated guidelines on tuberculosis: Fourth edition 158 Table A.2.3. Summary of the declarations of interest statements for the GDG: \u201cTargeted next-generation sequencing\u201d 2\u20135 May 2023 GDG member Interests declared Conclusion Nimalan Arinaminpathy Employment: Imperial College London. Consulting: Global Fund, WHO, WHO Regional Office for South-East Asia, Clinton Health Access Initiative, Copenhagen Consensus, Stop TB Partnership, USAID. Research support: Gates Foundation, US CDC, USAID, United Kingdom Medical Research Council. Member of various expert advisory bodies, the most relevant to this work being the regional Green Light Committee for the WHO South-East Asia Region, and the TB Strategic and Technical Advisory Group (STAG-TB) for WHO. Not significant conflict of interest David Branigan None declared No conflict of interest Daniela Cirillo Research support including the following: IMI Unite4TB, including coordinating microbiology workplan for clinical trials, monitoring of trials sites and retesting (ongoing); EUCAST, coordinating work for standard protocol for different TB drugs involving reference laboratories (ongoing); TB Alliance, unrestricted grant multipartner to test mic for pretomanid (ended 2020). No studies evaluating targeted NGS, no contracts paid by companies related to targeted NGS. Not significant conflict of interest Petra de Haas Research support including the following: funding for the evaluation of MinION (Oxford Nanopore Technologies), a 5-year KNCV project funded by a national postcode lottery, evaluating implementation and use of targeted NGS for diagnosis of multiple infectious diseases across three countries. Not significant conflict of interest Patricia Hall-Eidson Employed by the US CDC, as a funding organization to support TB research and oversee implementation of WHO TB policies and recommendations globally, including use of NGS for surveillance purposes. Not significant conflict of interest Rumina Hasan None declared No conflict of interest Sirinapha Jittimanee None declared No conflict of interest Kobto Koura None declared No conflict of interest Blessina Kumar None declared No conflict of interest", "Annex 2. Conflict of interest assessment for Guideline Development Group and External Review Group members 159 GDG member Interests declared Conclusion Nicole Menezes de Souza None declared No conflict of interest Jeremiah Chakaya Muhwa None declared No conflict of interest Norbert Ndjeka None declared No conflict of interest Mark Nicol Research support: Employer (University of Cape Town, South Africa) has received grant funding to conduct studies of a range of novel diagnostics for TB in children (including Xpert, LAM, RNAseq, and others). No funding for or studies of targeted NGS technologies. Not significant conflict of interest Thomas Shinnick Work as a consultant, through which contracts and travel support have been received from WHO, FIND and USAID for work related to laboratory strengthening and developing global guidance documents. Not significant conflict of interest Hojoon Sohn None declared No conflict of interest Sabira Tahseen None declared No conflict of interest Ezio Tavora dos Santos As an advocate and researcher working in community engagement in research and improvement of policies, the results of this work can potentially benefit the community with which he works. Not significant conflict of interest Nguyen Viet Nhung None declared No conflict of interest Elisabetta Walters Employment: Stellenbosch University, South Africa, no studies assessing or using targeted NGS technologies. Not significant conflict of interest Yanlin Zhao None declared No conflict of interest EUCAST: European Committee on Antimicrobial Susceptibility Testing; FIND: Foundation for Innovative New Diagnostics; GDG: Guideline Development Group; Global Fund: Global Fund to Fight AIDS, Tuberculosis and Malaria; IMI: Innovative Medicines Initiative; LAM: lipoarabinomannan antigen test; NGS: next-generation sequencing; TB: tuberculosis; United Kingdom: United Kingdom of Great Britain and Northern Ireland; USAID: United States Agency for International Development; US CDC: United States Centers for Disease Control and Prevention; WHO: World Health Organization.", "WHO consolidated guidelines on tuberculosis: Fourth edition 160 Table A.2.4. Summary of the declarations of interest statements for the ERG: \u201cTargeted Next-Generation Sequencing\u201d 2\u20135 May 2023 ERG member Interests declared Conclusion Nagalineswaran Kumarasamy None No conflict of interest Katharina Kranzer Employment at LSHTM; research support from EDCTP. Not significant conflict of interest Farzana Ismail Research support: Research Unit was included as one of the sites for the FIND Multi-centre Clinical Trial to Assess the Performance of Culture-free, End-to-end Targeted NGS Solutions for Diagnosis of Drug Resistant TB. Not significant conflict of interest Mitarai Satoshi None No conflict of interest John Metcalfe Research support from NIH; patent application entitled \u201cMethods for Producing Circular Deoxyribonucleic Acids\u201d. Not significant conflict of interest EDCTP: European and Developing Countries Clinical Trials Partnership; ERG: External Review Group; FIND: Foundation for Innovative New Diagnostics; LSHTM: London School of Hygiene & Tropical Medicine; NGS: next- generation sequencing; NIH: United States National Institutes of Health; TB: tuberculosis. Table A.2.4. Summary of the declarations of interest statements for the GDG: \u201cLow complexity nucleic acid amplification testing for detection of TB and resistance to rifampicin\u201d 6\u201310 May 2024 GDG member(s) Interests declared Conclusion David Branigan None declared No conflict of interest Jeremaya Chakaya Muhva None declared No conflict of interest Chamreun Sok Choub None declared No conflict of interest Katherine Fielding None declared No conflict of interest Rumina Hasan None declared No conflict of interest Kobto Gislain Koura None declared No conflict of interest Andrei Maryandyshev None declared No conflict of interest Norbert Ndjeka None declared No conflict of interest Thomas Shinnick None declared No conflict of interest Hojoon Sohn None declared No conflict of interest Sabira Tahseen None declared No conflict of interest NEW", "Annex 2. Conflict of interest assessment for Guideline Development Group and External Review Group members 161 GDG member(s) Interests declared Conclusion Timothy Walker None declared No conflict of interest Ou Xichao None declared No conflict of interest Daniela Cirillo Validation of the standard method for determination of MIC (BD/Jannsen), for research unit, ceased in 2023 Not significant conflict of interest Keertan Dheda Research grant to evaluate transcriptomic signature for BioMerieux (Awarded to UCT Lung Institute); Honoraria for being on speakers bureau or providing training Otsuka TB Drug; Honoraria for speakers on bureau (African Society of Laboratory Medicine) Cepheid \u2013 US$ 1200. Not significant conflict of interest Patricia Hall-Eidson All travel costs associated with meeting attendance were supported by the US CDC. Employed and salaried by the US President\u2019s Emergency Plan for AIDS Relief, a global health program that recommends, procures, and provides virtual and in-country technical assistance on TB low complexity automated nucleic acid amplification tests (and other TB assays) in low, moderate, and high burden countries to aid in TB case finding efforts among pediatric, adolescent, and adult persons living with HIV. Not significant conflict of interest Sirinapha Jittimanie Consultancy for GFATM country coordination mechanism in Thailand Not significant conflict of interest Katharina Kranzer Employment at LSHTM; Pretomanid consultancy for WHO; Research grant from EDCTP: ERASE-TB. In-kind contribution from Cepheid, SD-Biosensor for ERASE-TB. Not significant conflict of interest Shaheed Vally Omar Clinical Evaluation of the Xpert MTB/RIF assay using the GeneXpert OMNI; Clinical Evaluation of the Xpert\u00ae MTB/XDR Assay; Head-to-Head Evaluation of the CAT-A Enzyme Xpert MTB/RIF Ultra test vs. the Current on Market Xpert MTB/RIF Ultra V2 test, Cepheid, USD 66,390, for research unit, ceased in 2023. Not significant conflict of interest", "163 Annex 3. GDG members expertise, region, gender Table A.3.1. Guideline development group members: \u201cTargeted next-generation sequencing\u201d 2\u20135 May 2023 GDG member Expertise WHO region Gender Nimalan Arinaminpathy TB epidemiological moeling European Region M David Branigan Patient rights; Community care; TB detection and diagnosis Region of the Americas M Daniela Cirillo TB laboratory diagnosis European Region F Petra de Haas TB laboratory diagnosis European Region F Patricia Hall-Eidson TB laboratory diagnosis Region of the Americas F Rumina Hasan TB laboratory diagnosis Eastern Mediterranean Region F Sirinapha Jittimanee TB nursing care Western Pacific Region F Kobto Koura TB treatment European Region M Blessina Kumar Patient rights; Community care South-East Asia Region F Nicole Menezes de Souza TB laboratory diagnosis Region of the Americas F Jeremiah Chakaya Muhwa TB detection and diagnosis/ TB treatment African Region M Norbert Ndjeka TB treatment African Region M Mark Nicol TB diagnostics research Western Pacific Region M Thomas Shinnick TB laboratory diagnosis Region of the Americas M Hojoon Sohn Health Economics Western Pacific Region M", "WHO consolidated guidelines on tuberculosis: Fourth edition 164 GDG member Expertise WHO region Gender Sabira Tahseen TB laboratory diagnosis Eastern Mediterranean Region M Ezio Tavora dos Santos Patient rights; Community care; TB detection and diagnosis Region of the Americas M Nguyen Viet Nhung TB program management Western Pacific Region M Elisabetta Walters Pediatric TB diagnosis and treatment African Region F Yanlin Zhao TB program management Western Pacific Region M GDG: Guideline Development Group; WHO: World Health Organization. Table A.3.2. Summary of the declarations of interest statements for the GDG: \u201cLow complexity nucleic acid amplification testing for detection of TB and resistance to rifampicin\u201d 6\u201310 May 2024 GDG member Expertise WHO Region Gender David Branigan Patient advocacy and rights; Community care; TB detection and diagnosis Region of the Americas M Jeremaya Chakaya Muhva TB detection and diagnosis/ TB treatment African Region M Chamreun Sok Choub Patient advocacy and rights Western Pacific Region M Katherine Fielding TB epidemiology and data science European Region F Rumina Hasan TB laboratory diagnosis Eastern Mediterranean Region F Kobto Gislain Koura TB treatment European Region M Andrei Maryandyshev TB clinical management and treatment European Region M Norbert Ndjeka TB program management African Region M Thomas Shinnick TB laboratory diagnosis Region of the Americas M Hojoon Sohn Health Economics Western Pacific Region M NEW", "Annex 3. GDG members expertise, region, gender 165 GDG member Expertise WHO Region Gender Sabira Tahseen TB laboratory diagnosis Eastern Mediterranean Region M Timothy Walker TB laboratory diangosis and treatment European Region M Ou Xichao TB laboratory diagnosis Western Pacific Region M Daniela Cirillo TB laboratory diagnosis European Region F Keertan Dheda TB treatment African Region M Patricia Hall-Eidson TB laboratory diagnosis Region of the Americas F Sirinapha Jittimanie Patient advocacy and rights; Community care; Health program management (Nursing) Southeast Asia Region F Katharina Kranzer TB epidemiology and treatment European Region F Shaheed Vally Omar TB laboratory diagnosis African Region M", "\u00a9 World Health Organization 2016 All rights reserved. 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WHO/HTM/TB/2016.20 WHO Library Cataloguing-in-Publication Data Chest radiography in tuberculosis detection \u2013 summary of current WHO recommendations and guidance on programmatic approaches. I. World Health Organization. ISBN 978 92 4 151150 6 Subject headings are available from WHO institutional repository", "1 Chest radiography in tuberculosis detection T able of Contents Preface 2 Development process 3 Acknowledgements 4 Declarations of interests 4 Abbreviations 5 Definitions 5 1. INTRODUCTION 6 1.1 Medical imaging 6 1.2 Radiography 6 1.3 Chest X -ray for detecting TB 6 1.4 Overview of the use of chest X -ray in WHO\u2019s policies and guidelines 7 2. CHEST X -RAY AS A TRIAGE TOOL 10 2.1 Definition of triaging 10 2.2 T riaging for TB among people with respiratory complaints 10 2.3 TB triage algorithm options 12 3. CHEST X -RAY AS A DIAGNOSTIC AID 17 3.1 Chest X -ray as a diagnostic aid for respiratory and other intrathoracic diseases 17 3.2 Chest X -ray as a complement to bacteriological TB tests 17 3.3 Chest X -ray as part of a comprehensive diagnostic pathway in children 18 4. CHEST X -RAY AS A SCREENING TOOL FOR PULMONARY TB 20 4.1 Chest X -ray as a sensitive tool for screening for active TB 20 4.2 Chest X -ray screening in TB prevalence surveys 22 4.3 Chest X -ray to rule out active TB before treating latent infection 24 5. TECHNICAL SPECIFICA TION, QUALITY ASSURANCE, QUALITY CONTROL, AND SAFETY 25 5.1 T echnologies for chest X-ray and technical specifications 25 5.2 How to choose chest X -ray technology 26 5.3 Computer -aided detection of TB 26 5.4 Quality assurance and quality control 28 5.5 Safety 29 6. STRA TEGIC PLANNING FOR USING CHEST X-RAY IN NATIONAL TB CARE 31 Annexes 34 Annex 1. Yield and costs of triage algorithms in a hypothetical population of 100 000 with different TB prevalence levels 34 Annex 2. Proportion of TB cases detectable through screening with chest X-ray or by screening for chronic cough 37 References 38", "2 Chest radiography in tuberculosis detection Preface The End TB Strategy puts renewed emphasis on the need to ensure early and correct diagnosis for all people with tuberculosis (TB) (1). Important progress has been made in improving laboratory services in recent decades. New bacteriological tests for TB diagnosis have become available and their use is now being scaled up (2, 3). Efforts have been made to ensure that people who seek care and have symptoms consistent with TB are correctly triaged and evaluated for TB. Systematic screening for active TB in high- risk groups is being implemented and scaled up in several places (4, 5). However, despite these efforts, many people with TB remain undiagnosed or are diagnosed only after long delays (6). Chest radiography, or chest X-ray (CXR), is an important tool for triaging and screening for pulmonary TB, and it is also useful to aid diagnosis when pulmonary TB cannot be confirmed bacteriologically. Although recent diagnostic strategies have given specific prominence to bacteriology, CXR can be used for selecting individuals for referral for bacteriological examination, and the role of radiology remains important when bacteriological tests cannot provide a clear answer. Access to high-quality radiography is limited in many settings. Ensuring the wider and quality-assured use of CXR for TB detection in combination with laboratory- based diagnostic tests recommended by the World Health Organization (WHO), can contribute to earlier TB diagnosis and potentially to closing the TB case-detection gap when used as part of algorithms within a framework of health-system and laboratory strengthening. This document summarizes WHO\u2019s recommendations on using CXR for TB triaging, diagnosis and screening. It also outlines a framework for the strategic planning and use of CXR within national TB programmes (NTP). Moreover, the document provides a brief overview of technical specifications, and quality assurance and safety considerations for CXR. However, because these technical aspects are generic and should be addressed as part of the general strengthening of radiography and imaging services, this document does not go into technical details. General radiography guidance is provided elsewhere (7-11). The document focuses on CXR, with a major emphasis on detecting pulmonary TB. CXR can be useful for diagnosing other forms of TB (for example, miliary or pericardial TB, or tuberculous effusions) and other imaging techniques are also valuable for TB diagnosis, for example, for extrapulmonary TB, but these topics are not discussed in this document. The document is", "3 Chest radiography in tuberculosis detection Development process A steering group was established in January 2016, which advised WHO on the scope and content of this document. The members of the steering group were Faiz Ahmad Khan, Sevim Ahmedov, Frank Cobelens, Jacob Creswell, Claudia Denkinger, Christopher Gilpin, Michael Kimerling, Knut L\u00f6nnroth, Cecily Miller, YaDiul Mukadi, Ikushi Onozaki and Madhukar Pai. After consultation with WHO\u2019s Guideline Review Committee, it was determined that the document is not a new guideline but a summary of existing WHO recommendations. Therefore, it did not need to follow WHO\u2019s guideline development process. All major WHO publications about TB were reviewed for their relevance to the use of CXR in screening for, triaging and diagnosing TB. Recommendations across all documents were compiled and summarized. An accompanying framework for strategic planning for using CXR within NTPS was developed based on experts\u2019 opinions. No systematic literature review was undertaken during the development of this document. The evidence base for the statements made in this document is the same as for those in the cited WHO guidelines and policy frameworks. Scenarios for the yield of TB (true positive/true negative and false positive/false negative) for different triaging algorithms were modelled using the ScreenTB tool (12) to illustrate how the different placement of CXR in an algorithm influences yields and costs under different epidemiological scenarios. The model outputs that are included in this document should not be used for forecasting TB detection, but are included merely to demonstrate how variations in algorithms influence TB detection and costs. Readers are advised to develop setting-specific scenarios based on the local TB epidemiology and the best data about test accuracy and costs. A first draft was completed in July 2016 and was circulated to experts (see below) for peer review. Based on comments from the peer review, a second draft was prepared ahead of a global consultation held during 28\u201329 September 2016. The consultation provided additional inputs on the draft document, and the documented was thereafter finalized.", "4 Chest radiography in tuberculosis detection Acknowledgements The first draft was prepared by Cecily Miller and Knut L\u00f6nnroth. The following persons contributed to the development of the document or peer reviewed it, or both: Faiz Ahmad Khan, Sevim Ahmedov, Farhana Amanullah, Samiha Baghdadi, Draurio Barreira, Adriana Velazquez Berumen, Nils Billo, Annemieke Brands, Grania Brigden, Chen-Yuan Chiang, Maarten van Cleeff, Jacob Creswell, Claudia Denkinger, Anna-Marie Celina Garfin, Nebiat Gebreselassie, Sifrash Meseret Gelaw, Wayne van Gemert, Robert Gie, Steve Graham, Rob van Hest, Philip Hopewell, Bogomil Kohlbrenner, Alexei Korobitsyn, Devesh Gupta, Michael Kimerling, Irwin Law, Partha Pratim Mandal, Guy Marks, Giovanni Batista Migliori, Mahshid Nasehi, Nobuyuki Nishikiori, Pierre-Yves Norval, Kosuke Okada, Ikushi Onozaki, Salah-Eddine Ottmani, Madhukar Pai, Tripti Pande, Mario Raviglione, Maria del Rosario P\u00e9rez, Anna Scardigli, Eric Stern, Beat Stoll, Etienne- Leroy T erquem, Belay T essema, Mukund Uplekar, Diana Weil, William Wells, Marieke van der Werf and Christine Whalen. Declarations of interests The following interests were declared by the experts consulted. Declared interests that were deemed not significant \u2022 Claudia Denkinger: took part in several clinical research projects to evaluate new diagnostic tests against the target product profiles for TB defined through consensus processes led by WHO. These studies were for diagnostic products developed by private sector companies (Cepheid, Epistem, Molbio Diagnostics, Hain Lifescience, Nipro, Becton Dickinson, Alere, YD Diagnostics, Ustar Biotechnologies and Qiagen) that provide access to know-how, equipment and reagents, and contribute through unrestricted donations as per FIND (Foundation for Innovative New Diagnostics) policy. \u2022 Bogomil K ohlbrenner and Beat Stoll: were employed as researchers on a project to develop appropriate medical devices and appropriate training for health workers in the field of tropical medical imaging; it was a philanthropic project. Declared interest that were deemed significant for making recommendations to WHO about whether to develop guidelines for computer-aided detection \u2022 F aiz Ahmad Khan and Madhukar Pai: received a research grant to study the diagnostic accuracy of CAD4TB (developed by Delft Imaging Systems, Veenendaal, the Netherlands) in collaboration with Interactive Research & Development, who have purchased equipment from the makers of CAD4TB. The developers of CAD4TB are not collaborators or in any way involved in the research. Faiz Ahmad Khan and Madhukar Pai were invited to present the systematic review on CAD for TB detection, provide comments throughout the meeting, and peer-review draft documents. However, they were not part of the decision to advise WHO on the", "5 Chest radiography in tuberculosis detection Abbreviations AFB acid-fast bacilli CAD computer -aided detection CXR chest X -ray or chest radiography HIV human immunodeficiency virus L TBI latent tuberculosis infection MTB Mycobacterium tuberculosis NTP national tuberculosis programme PICO population, intervention, comparator , outcome QUADAS Quality Assessment of Diagnostic Accuracy Studies S SM sputum-smear microscopy TB tuberculosis WHO W orld Health Organization Definitions Bacteriologically confirmed TB case: A bacteriologically confirmed case of TB is one from whom a biological specimen tests positive by smear microscopy, culture or WHO-recommended rapid diagnostic (such as the Xpert MTB/RIF assay). All such cases should be notified, regardless of whether TB treatment has started (13). Clinically diagnosed TB case: A clinically diagnosed case of TB is one who does not fulfil the criteria for bacteriological confirmation but has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give the patient a full course of anti-TB treatment. This definition includes cases diagnosed on the basis of abnormalities seen on X-ray or histology suggestive of TB, and extrapulmonary cases without laboratory confirmation. Clinically diagnosed cases subsequently found to be bacteriologically positive (before or after starting treatment) should be reclassified as bacteriologically confirmed (13). Systematic screening for active TB: is the systematic identification of people with suspected active TB in a predetermined target group, using tests, examinations or other procedures that can be applied rapidly (4). Unlike evaluations of those who actively seek care for respiratory symptoms (known as triaging), the systematic screening of individuals for TB is typically initiated by a provider and offered in a systematic way to an apparently healthy target group that has been determined to have a high risk of TB. Triaging: For the purpose of this document, triaging is defined as the processes of deciding the diagnostic and care pathways for people seeking healthcare, based on their symptoms, signs, risk markers and test results. Triaging involves assessing the likelihood of various differential diagnoses as a basis for making clinical decisions. It can follow more- or less-standardized protocols and algorithms and may be done in multiple steps.", "6 Chest radiography in tuberculosis detection 1. INTRODUCTION 1.1 Medical imaging Medical imaging uses different modalities and processes to image the internal structures of the human body for diagnosis and treatment. Imaging has an important role in healthcare for all population groups. In public health and preventive medicine, as well as in both curative and palliative care, effective clinical decisions depend on correctly screening, triaging and diagnosing patients. The use of imaging services is paramount in correctly screening, confirming and documenting the course of many diseases. With the improved availability of medical equipment, global access to medical imaging has increased considerably, but is still insufficient in many settings (14). Medical imaging is a key element within many evidence-based clinical decision-support algorithms, consistent with overarching evidence-based recommendations for disease management (14). As such, medical imaging should be accessible to all and should not be exclusively a hospital service (15). 1.2 Radiography Radiography uses X-rays to visualize the internal structures of a patient. X-rays are a form of electromagnetic radiation produced by an X-ray tube. The X-rays pass through the body and are captured behind the patient by film that is sensitive to X-rays or by a digital detector. Different tissues in the body vary in their absorption of X-rays: dense bone absorbs more radiation, but soft tissue allows more to pass through. This variance produces contrasts within the image to give a two-dimensional representation of the three-dimensional structures. As a result, the X-ray image often includes overlapping structures. A thorough knowledge of anatomy is needed to identify an abnormality on an X-ray and understand where it is in the body. Common clinical applications include imaging the chest to assess lung and intrathoracic pathologies; imaging the skeletal system to examine bone structures and diagnose fractures, dislocations or other bone pathologies; imaging the abdomen to assess obstructions or free air or fluid within the abdominal cavity; or imaging the teeth to assess common dental pathologies, such as cavities or abscesses (14). 1.3 Chest X-ray for detecting TB Chest X-ray (CXR) is a rapid imaging technique that allows lung abnormalities to be identified. CXR is used to diagnose conditions of the thoracic cavity, including the airways, ribs, lungs, heart and diaphragm. CXR has historically been one of the primary tools for detecting tuberculosis (TB), especially pulmonary TB. CXR has high sensitivity for pulmonary TB and thus is a valuable tool to identify TB as", "a differential diagnosis for patients, especially when the X-ray is read to identify any abnormality that is consistent with TB. However, CXR has poor specificity; although some CXR abnormalities are rather specific for pulmonary TB (for example, cavities), many CXR abnormalities that are consistent with pulmonary TB are seen also in several other lung pathologies and, therefore, are indicative not only of TB but also of other pathologies. Moreover, there is significant intra- and interobserver variation in the reading of CXRs. Relying only on CXR for TB diagnosis leads to overdiagnosis, as well as underdiagnosis (16). Rigorous efforts should always be made to base a TB diagnosis on bacteriological confirmation (sputum-smear microscopy, culture or a molecular test). WHO classifies TB diagnosis into bacteriologically confirmed TB, if it is based on bacteriological confirmation, or clinically diagnosed TB, if it is based on clinical assessment including CXR, but is not confirmed by bacteriological examination (13).", "7 Chest radiography in tuberculosis detection 1.4 Overview of the use of chest X-ray in WHO\u2019s policies and guidelines For many years, WHO has recommended CXR as a diagnostic tool to be used as a complementary part of the clinical diagnosis of bacteriologically negative TB. As such, CXR has previously been placed at the end of diagnostic algorithms. WHO\u2019s 2003 treatment guidelines for national programmes and the guideline on diagnosing smear-negative pulmonary TB from 2007 recommended that CXR be used after: (i) initial negative bacteriological testing, (ii) a course of broad-spectrum antibiotics and (iii) a second negative round of bacteriological testing (17, 18). However, CXR was recommended to be used directly after initial negative bacteriological testing to diagnose TB in people living with HIV or AIDS and in those considered to be at high risk of HIV infection(18). The 2008 handbook for national tuberculosis control programmes (19), as well as the third edition of the International standards for tuberculosis care in 2014 (20), suggested a more flexible approach, with the possibility of using CXR directly after an initial negative bacteriological test, and not just for people living with HIV . None of these guidelines placed CXR as a triage test before bacteriological testing. However, none of the guidelines specifically recommend against using CXR for triaging or diagnostic evaluation of TB, and they emphasized that whenever CXR has been done and shows abnormalities consistent with TB, a bacteriological test for TB must always be performed. All the above-mentioned documents emphasized that using CXR to diagnose TB is problematic, given that CXR has low specificity and significant interobserver variation. Moreover, poor access to high-quality radiography equipment and expert interpretation, along with the widespread use of low-quality radiography, were identified as additional barriers for promoting large-scale programmatic use. Recently, however, CXR has been promoted as a useful tool that can be placed early in screening and triaging algorithms. An important reason for rethinking the role of CXR in screening and diagnostic algorithms is that numerous national TB prevalence surveys have demonstrated that CXR is the most sensitive screening tool for pulmonary TB and that a significant proportion of people with TB are asymptomatic, at least early in the course of the disease (see Annex 2) (21). Other factors that have contributed to CXR becoming an increasingly accepted part of programmatic approaches to TB care and prevention include: \u2022 the increased availability of radiography,", "including digital radiography with its lower running costs and highly portable systems for field use, better image quality and better safety (due to decreased radiation dose) than conventional radiography, as well as possibilities for use for telemedicine; \u2022 the documented rapidity of results and high throughput capacity , especially of digital CXR; \u2022 a gradual shift from strictly prioritizing the diagnosis of the most infectious TB cases (that is, bacteriologically confirmed TB, especially sputum smear-positive TB, in persons with persistent cough) to programmatic targets in line with a rights-based vision of universal access to high-quality diagnosis for all people with all forms of TB as well as concern with diagnosis of other lung diseases; \u2022 the increasing availability of rapid molecular tests with higher sensitivity and specificity than sputum- smear microscopy which allows for higher diagnostic accuracy among people with CXR abnormalities consistent with TB (and, thus, reduces the risk of overdiagnosis). Moreover , available molecular tests have significantly higher costs than sputum smear microscopy, which often necessitates a method of triaging of patients for evaluation for TB.", "8 Chest radiography in tuberculosis detection The limitations of, and recent advances in, CXR are summarized in Box 1. BOX 1. Limitations of and advances in chest X-ray (21) The main limitations associated with using chest X-ray include: \u2022 it produces two-dimensional representations of a three-dimensional structure; \u2022 there is intrareader and interreader variability; \u2022 no abnormalities are definitive of TB, therefore the specificity is low; \u2022 a universally accepted reporting system is lacking; \u2022 patients are exposed to ionizing radiation; \u2022 special equipment (with adequate input power) is needed; \u2022 trained personnel are required to operate the machine and interpret the results; \u2022 there is often limited access in rural areas; access is often limited to district or regional levels; \u2022 there is limited archiving of hard copies; \u2022 out-of -pocket costs for patients are often high. Recent advances in digital chest X-ray technology include: \u2022 lower operating costs; \u2022 improved and more reproducible image quality with enlargement capability; \u2022 a decreased radiation dose; \u2022 improved portable systems that can be used for mobile units; \u2022 efforts to harmonize interpretation and reporting; \u2022 the potential of objective tools for interpretation of digital images, such as computer -aided detection; \u2022 better (digital) archiving facilities; \u2022 film processing equipment and hard copies no longer required; \u2022 the possibility of electronically transmitting images (for example, for telemedicine or quality assurance). The importance of CXR is reflected by the recommendations about using CXR for screening, triaging and assisting in the diagnosis of TB that have been included in recent policies developed or endorsed by WHO , including: \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Guidance for national tuberculosis programmes on the management of tuberculosis in children (22) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 the implementation manual for the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA , United States) (3) \u2022 International standards for tuberculosis care, third edition (20) \u2022 Guidelines on the management of latent tuberculosis infection (24). Box 2 summarizes the recent recommendations from WHO. However, despite the demonstrated utility of CXR and multiple WHO recommendations about when and how to use it, the programmatic and rational use of CXR for TB detection remains limited. The lack of consolidated programmatic guidance is one possible reason, hence the need for this", "document. Also contributing to its restricted use are the limited availability of radiography in some regions (including a lack of systems and incentives to keep X-ray machines operational), constraints on human resources, insufficient training (including qualification programmes and post-graduate training), a lack of quality assurance programmes and, often, high out-of-pocket costs for patients. In the following chapters, the options for using CXR for different elements of TB detection are outlined in more detail. This is followed by a brief summary of technical specifications, and quality control and safety issues. Finally, guidance on the programmatic planning and implementation of CXR is discussed.", "9 Chest radiography in tuberculosis detection BOX 2. Summary of recommendations on using chest X-ray (CXR) for TB in recent WHO guidelines and policies CHEST X-RAY: AN ESSENTIAL TOOL TO END TB CXR IS A SENSITIVE TOOL FOR SCREENING FOR ACTIVE TB Reference: Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 CXR has higher sensitivity for pulmonary TB than screening for TB symptoms. AN ABNORMAL CXR IS AN INDICA TION FOR FULL DIAGNOSTIC EVALUATION Reference: International standards for tuberculosis care (20) \u2022 All patients with unexplained fi ndings suggestive of TB on CXR should be evaluated for TB with a bacteriological diagnostic test. \u2022 CXR can be used as a supplementary diagnostic aid, although the specificity is low . \u2022 A bacteriologically confirmed diagnosis is always preferred. CXR IS AN IMPORT ANT TOOL FOR DIAGNOSING CHILDHOOD TB Reference: Guidance for national tuberculosis programmes on the management of tuberculosis in children (22) \u2022 CXR is useful in diagnosing pulmonary and extrapulmonary TB in children in combination with history , evidence of TB infection and microbiological testing. CXR CAN IMPROVE THE EFFICIENCY OF USING THE XPERT MTB/RIF ASSAY Reference: implementation manual for the Xpert MTB/RIF assay (3) \u2022 CXR and further clinical assessment can be used to triage who should be tested with the Xpert MTB/RIF assay to reduce the number of individuals tested and the associat ed costs, as well as to improve the pre- test probability for TB and, thus, the predictive value of the Xpert MTB/RIF assay. CXR CAN ASSIST IN DIAGNOSING TB AMONG PEOPLE LIVING WITH HIV Reference: Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 CXR can assist in diagnosing TB among people living with HIV . It is particularly useful for ruling out TB disease before providing treatment for latent TB infection. CXR HELPS RULE OUT ACTIVE TB BEFORE TREATING LATENT TB INFECTION Reference: Guidelines on the management of latent tuberculosis infection (24) \u2022 CXR used in combination with symptom screening has the highest sensitivity for detecting TB and, thus, should be used to exclude active TB before initiating treatment o f latent TB infection. \u2022 Individuals with any radiological abnormality or TB symptoms should be investigated further for active TB and other conditions. CXR IS AN ES SENTIAL TECHNOLOGY FOR PREVALENCE SURVEYS Reference: Tuberculosis prevalence surveys: a handbook (21) \u2022 CXR is a necessary screening", "tool to identify survey participants eligible for bacteriological examination; in recent surveys, CXR has proven essential for detecting a large pr oportion of prevalent TB cases. More information can be found in the following resources: \u2022 WHO\u2019s diagnostic imaging website (14) \u2022 The WHO manual of diagnostic imaging: radiographic anatomy and interpretation of the chest and the pulmonary system (7) \u2022 International standards for tuberculosis care, third edition (20) - Standards for TB care in India (25) - European Union standards for tuberculosis care (26) - Canadian tuberculosis standards, seventh edition (27) \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Systematic screening for active tuberculosis: an operational guide (5) \u2022 Guidelines on the management of latent tuberculosis infection (24) \u2022 Guidance for national tuberculosis programmes on the management of tuberculosis in children, second edition (22) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 Xpert MTB/RIF implementation manual (3) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 P ocket book of hospital care for children (28) \u2022 the website for the Practical approach to Lung Health (known as P AL) (29).", "10 Chest radiography in tuberculosis detection 2. CHEST X-RAY AS A TRIAGE TOOL 2.1 Definition of triaging For the purpose of this document, triaging is defined as the processes of deciding the diagnostic and care pathways for people seeking healthcare, based on their symptoms, signs, risk markers and test results. Triaging involves assessing the likelihood of various differential diagnoses as a basis for making clinical decisions. It can follow more- or less-standardized protocols and algorithms and may be done in multiple steps. Effective triaging that helps to rapidly identify TB is important both for optimizing care for the individual and for ensuring good infection control (30). Triaging protocols should be adapted to the disease\u2019s epidemiology in a given setting because the prevalence of different diseases determines the predictive values of symptoms, signs, risk markers and test results. Triaging is different from systematic screening in that it focuses on the clinical management of a person seeking healthcare for one or several unexplained complaints or concerns, while systematic screening normally is initiated by a provider and targets apparently healthy individuals with or without risk markers for a given disease; for more information on systematic screening see Systematic screening for active tuberculosis: principles and recommendations (4) and the associated Systematic screening for active tuberculosis: an operational guide (5). 2.2 Triaging for TB among people with respiratory complaints Proper triaging of people seeking healthcare with respiratory complaints is essential for diagnosing TB correctly and early, as well as for the early diagnosis of other conditions. Unfortunately, not all people seeking care with symptoms consistent with TB receive an adequate evaluation for TB. These failures result in missed opportunities for detecting TB early and lead to increased disease severity, more complications and a higher risk of poor treatment outcomes for the patients. They also can lead to a greater overall disease burden in the community because they increase the likelihood of transmission of Mycobacterium tuberculosis in health facilities and to family members and others in the community. For this reason, effective and efficient clinical triaging algorithms are of utmost importance; for more information see the International standards for tuberculosis care (20). People with pulmonary TB who are seeking care often initially present with non-specific respiratory symptoms that need to be evaluated. Respiratory conditions are among the most common acute and chronic diseases worldwide; they occur in all societies and in all age groups. The heavy", "burden of respiratory diseases means that their symptoms are some of the most common reasons why patients seek primary healthcare: respiratory complaints (including cough, sputum production, and shortness of breath) often constitute around 20% of the symptoms that prompt a visit to a primary health centre (31); for more information see the website for the Practical approach to Lung Health (known as PAL) (29). Thus, respiratory symptoms are both common and non-specific. Most people with respiratory symptoms consistent with TB do not have TB, even in setting where TB is highly endemic. Therefore, it is important to identify in a sensitive and efficient manner those who have a high likelihood of TB among those with respiratory symptoms and to determine the underlying cause of disease for those who are not ultimately diagnosed with TB. Triage algorithms that are appropriate to specific patient populations, the epidemiology of respiratory conditions, and healthcare-system capacity are essential for providing high-quality care. Where it is available and feasible in the outpatient primary care setting, CXR can be used as an effective triage test for those seeking care for respiratory complaints. CXR is a sensitive tool for identifying TB, meaning that it identifies most people with a high likelihood of having the disease, while correctly ruling out TB in most persons when the X-ray is read to look for any abnormality consistent with TB. In addition, CXR can help identify other pulmonary conditions, such as lung cancer and occupational lung diseases like silicosis, as well as other intrathoracic diseases that require further diagnostic evaluation. Therefore, CXR is a useful general triage test for pulmonary conditions because it helps identify which type of further diagnostic evaluation patients require to correctly diagnose the cause of their illness. A normal CXR helps", "11 Chest radiography in tuberculosis detection rule out a number of pulmonary conditions and prompts diagnostic evaluation for conditions consistent with no radiological findings, while an abnormal CXR prompts evaluation for conditions consistent with radiographic changes, including but not limited to bacteriological evaluation for TB (Fig. 1). In any case, when used as a triage test, CXR should be followed by further diagnostic evaluation to establish a diagnosis. Generating differential diagnoses for conditions other than TB may be the primary objective of ordering a CXR. Regardless of the reason for obtaining a CXR, it is important that any CXR abnormality consistent with TB be further evaluated with a bacteriological test (20). FIG. 1. Using chest radiography as a triage tool AFB: acid-fast bacilli; CXR: chest X-ray; MTB: Mycobacterium tuberculosis, TB: tuberculosis. CXR may have higher specificity for pulmonary TB than assessing symptoms alone, depending on how the X-ray is read. Therefore, triaging using CXR can help reduce the number of persons who undergo bacteriological TB testing without decreasing the detection of true TB cases. CXR also improves the positive predictive value of subsequent bacteriological tests by increasing the pre-test probability of TB (4). Beyond identifying active TB disease, CXR also identifies one of the populations at highest risk of developing TB disease: those who have inactive TB or fibrotic lesions without a history of TB treatment. Once active TB has been excluded, patients with fibrotic lesions should be followed-up, given their high risk for developing active disease (4). There is no comprehensive WHO guidance on using CXR in triaging individuals with respiratory symptoms. In the absence of such guidance, this chapter presents options for approaches to triage, and the contribution of CXR to each approach is described. Indication for CXR Additional evaluation as indicated CXR Normal Consistent with TB Bacteriological evaluation of TB AFB or MTB present Abnormal Not consistent with TB AFB or MTB not present", "12 Chest radiography in tuberculosis detection 2.3 TB triage algorithm options In this section, different triage algorithms for patients with respiratory complaints are discussed (up to the point of ordering an initial bacteriological test for TB) and compared to help guide the choice of an appropriate algorithm for different situations. At the end of the section, the algorithms are displayed schematically, together with indications of the yield of true positives and false positives for TB and the cost per true TB case detected, based on modelled yields and costs in a hypothetical scenario in which the prevalence of TB is 0.5% (500 cases/100 000 population) among persons entering the triage algorithm (Fig. 2). Details and additional scenarios are provided in Annex 1. The estimated yield shown concerns only bacteriologically confirmed TB, and the yield of false-positive TB corresponds to a false positive only on initial bacteriological testing. Actions to be taken after a positive or negative initial bacteriological test \u2013 including further evaluation for TB, drug resistance and for other underlying conditions, as well as the yield of true-positive and false-positive TB based on clinical diagnosis \u2013 are discussed in Section 2.3.3. and Chapter 3. In line with the progressive realization of universal health coverage, out-of-pocket expenditures for CXR, as well as for bacteriological and other tests, should be minimized (32). Costs should be covered through fair third-party financing. If CXR is used for triaging and the subsequent diagnostic evaluation of patients with respiratory complaints, CXR and bacteriological tests should be free of charge for patients. The algorithm scenarios discussed here and displayed in Fig. 2 and in Annex 1 assume there are no direct costs for patients and estimate the potential magnitude of costs from a healthcare perspective of various approaches to triaging for TB, including using CXR and other tools. When tools are available only on the referral level, additional indirect costs for patients, as well as transport, feasibility and time factors, need to be considered when choosing an appropriate algorithm. Further discussion of CXR infrastructure, planning and financing can be found in Chapter 6. 2.3.1 Optimizing TB triaging when sputum-smear microscopy is used as bacteriological test Traditionally, chronic and productive cough (with a duration of longer than 2\u20133 weeks) has been used by national tuberculosis programmes (NTPs) as a triaging criterion for determining who should undergo sputum-smear microscopy (Algorithm 1). This approach identifies people with an advanced", "stage of TB, and it is a rational public health approach when the priority is to detect highly infectious pulmonary TB or when CXR is not available. If available, CXR can be used as an additional triage test after initially triaging for chronic cough (Algorithm 2). Because CXR is sensitive, Algorithm 2 has a similar yield to Algorithm 1 of true-positive cases detected with sputum-smear microscopy while reducing the number of persons who need to undergo sputum-smear microscopy. However, the cost can be higher, depending on the cost of CXR as compared with the cost of sputum-smear microscopy. The number of false-positive sputum- smear microscopy results is low for both of these algorithms when the TB prevalence is moderate to high, although it is lower in Algorithm 2, which includes CXR. However, introducing CXR before a bacteriological test can increase the total number of clinically diagnosed cases and, thus, also the total number of false- positive cases, depending on what further diagnostic evaluation and treatment decisions are made for patients with abnormal CXR and negative bacteriological tests (see Section 2.3.3. and Chapter 3). Triage algorithms based on chronic cough have a low sensitivity for TB, and, thus, many cases will be missed with this approach, especially in the early stages of disease. Recent TB prevalence surveys have demonstrated that a large proportion of people with bacteriologically confirmed TB do not experience chronic cough (21). Annex 2 shows the proportion detectable through screening with CXR and screening for chronic cough among persons with bacteriologically confirmed TB detected in recent TB prevalence surveys. Earlier and more complete detection of TB among people seeking healthcare may, therefore, require bacteriological testing for TB using broader indications, especially in TB-endemic settings. This may include testing all people with any symptom or sign consistent with TB (that is, any one of cough, haemoptysis, fever, night sweats or weight loss) as in Algorithm 3, or testing those with a predefined constellation of symptoms, signs and clinical or population-based risk markers for TB (for example, HIV , other immune- compromising conditions, diabetes, renal failure, smoking, alcohol or substance abuse, undernutrition, poverty, homelessness, history of imprisonment, migration from a TB-endemic setting). The appropriate threshold or indication for applying a bacteriological test depends on the local TB epidemiology. As a guiding principle, the higher the TB prevalence, the broader the indication for TB testing should be.", "13 Chest radiography in tuberculosis detection T esting using a broad indication, such as any symptom consistent with TB, increases the total yield of TB cases detected. However, it can lead to high demands on resources and overloaded laboratories. It also leads to a lower positive predictive value for the bacteriological test result and, thus, a higher risk of false-positive test results. Narrowing symptom criteria will, in most situations, lower the sensitivity while increasing the specificity, and reduce the number who need to undergo bacteriological testing. Using CXR as an additional triage test is especially useful in the context of more inclusive initial symptom triaging, and it can lead to a high total yield with fewer bacteriological tests per detected case and fewer false- positive sputum-smear microscopy results as compared with symptom screening alone (see Algorithm 4). However, introducing CXR into an algorithm that uses smear microscopy as the bacteriological test can increase the cost per true case detected, depending on the relative costs of CXR and microscopy. It can also increase the number of clinically diagnosed cases, of which a substantial proportion may be false positives if proper quality control of clinical diagnosis is not in place (see Section 2.3.3. and Chapter 3). Algorithm 5 uses CXR as an initial triage test (regardless of symptoms, signs and other risk markers), which has been suggested as a rigorous triaging approach for healthcare facilities in some hyperendemic settings). It improves the sensitivity of triaging as compared with initial symptom-based triaging and, thus, improves case detection, but it can increase resource demands considerably, including for laboratories. Such an approach is equivalent to systematic TB screening in health facilities, which is further discussed in Chapter 3. 2.3.2 Chest X-ray triaging to optimize use of the Xpert MTB/RIF assay As NTPs adopt and roll out the Xpert MTB/RIF assay into routine practice for TB diagnosis, it becomes important to determine how the test can be most efficiently used in evaluating patients with suspected TB; for more information see the Xpert MTB/RIF implementation manual (3). In Algorithm 6, replacing sputum-smear microscopy with the Xpert MTB/RIF assay as the primary bacteriological test after initial triaging for chronic cough increases the yield of bacteriologically confirmed TB. However, the cost per true case detected is considerably higher than with an algorithm using sputum- smear microscopy due to the higher costs for the Xpert MTB/RIF assay. One approach to", "reducing the number of individuals who undergo Xpert MTB/RIF testing without significantly reducing the yield of TB cases detected is to use Algorithm 7; in this algorithm CXR is used as a second triage test after initial triaging for chronic cough, after which patients with abnormal CXR results are referred for Xpert MTB/RIF testing for confirmatory diagnostic evaluation. If CXR is readily available and considerably cheaper than Xpert MTB/RIF testing, which is often the case, especially with digital CXR, this could greatly reduce the cost per true case detected. CXR triaging also increases the positive predictive value of Xpert MTB/RIF testing. The specificity of the Xpert MTB/RIF assay for detecting TB is high (99%, with liquid culture as reference standard) (2). However, given that it is not 100%, the positive predictive value of Xpert MTB/ RIF testing may be low when applied to groups with a relatively low TB prevalence. Using CXR as a triage test for those who have chronic cough and then referring those with abnormal results for confirmatory testing with the Xpert MTB/RIF assay results in a higher prevalence of TB in the group tested and, thus, increases the positive predictive value and minimizes false-positive results. Using CXR as a triage test is further discussed in the Xpert MTB/RIF implementation manual (3). However, the sensitivity of Algorithms 6 and 7 remains limited due to the low sensitivity of the initial triaging for chronic cough. In order for Xpert MTB/RIF testing to significantly improve early TB detection it may need to be used with a broad indication. Using Xpert MTB/RIF testing as the primary diagnostic test after triaging for any TB symptoms is a highly sensitive approach (see Algorithm 8). However, this algorithm is expensive and requires high-throughput capacity for Xpert MTB/RIF testing. Using CXR as a second triage test is especially valuable when the initial triaging is for any TB symptom (see Algorithm 9). Algorithm 9 can significantly reduce the laboratory burden, cost per true case detected and false-positive bacteriological test results. As discussed in Section 2.3.1, introducing CXR before a bacteriological test can increase the total number of clinically diagnosed cases and, thus, also the total number of false-positive cases, depending on what further evaluation and treatment decisions are made for patients with abnormal CXR and negative bacteriological tests. This is more likely when sputum-smear microscopy is used than when Xpert MTB/", "14 Chest radiography in tuberculosis detection RIF testing is used because the Xpert MTB/RIF assay is more sensitive and, therefore, has a much higher negative predictive value than sputum-smear microscopy. This means that the likelihood is low that a person with a negative Xpert MTB/RIF test has TB. It is important that clinicians interpret a negative Xpert MTB/RIF result differently than a negative sputum-smear microscopy result. Although no bacteriological test can completely rule out TB, a clinical diagnosis needs to be considered for a much smaller proportion of persons who are negative by Xpert MTB/RIF testing than for persons who are negative by sputum-smear microscopy (see Chapter 3). The most sensitive algorithm is to use CXR for initial triaging regardless of symptoms, followed by Xpert MTB/RIF testing (see Algorithm 10). However, this algorithm is more expensive and results in a higher number of false-positive results than sequential triaging with symptoms and CXR. FIG. 2. Algorithm options for triaging patients with respiratory complaints consistent with TB a Triage algorithm Cost per true case detected Yield of true-positive results Yield of false-positive results 1. Cough followed by microscopy 2. Cough followed by CXR followed by microscopy 3. Any TB symptom followed by microscopy 4. Any TB symptom followed by CXR followed by microscopy 5. CXR followed by microscopy 6. Cough followed by Xpert MTB/RIF testing 7. Cough followed by CXR followed by Xpert MTB/RIF testing 8. Any TB symptom followed by Xpert MTB/RIF testing 9. Any TB symptom followed by CXR, followed by Xpert MTB/RIF testing 10. CXR followed by Xpert MTB/RIF testing CXR: chest X-ray.", "15 Chest radiography in tuberculosis detection a The figure shows the potential yield of triage and the subsequent diagnostic evaluation for TB based on using the indicated tools. The cost and yield indicator values are based on a hypothetical scenario of a triage population of 100 000 with a TB prevalence of 0.5% (500 cases/100 000 population). (Details are available in Annex 1.) The Cost indicator ($) corresponds to the cost per true case detected for each algorithm; $ corresponds to the algorithm with the lowest relative cost per true case detected and $$$$$ corresponds to the algorithm with the highest cost per true case detected. The True-positives indicator (green +) corresponds to the yield of true TB cases (with liquid culture as the gold standard); one green + corresponds to the algorithm with the lowest yield of true-positive cases and five green +++++ signs correspond to the algorithm with the highest yield of true-positive cases. The False-positives indicator (red +) corresponds to the number of false-positive bacteriological test results; one red + corresponds to the algorithm with the lowest number of false-positive test results and five red +++++ signs correspond to the algorithm with the highest number of false-positive results. Note that true and false positive indicators within each algorithm are not proportional and can therefore not be directly compared to assess positive predictive values. Also note that predictive values change with prevalence. See Annex 1 for actual numbers with different prevalence. 2.3.3 Using chest X-ray after a negative bacteriological test result A negative initial bacteriological test result may require additional bacteriological testing (see Chapter 3). This can be done in parallel with a CXR if CXR was not done previously. For the diagnosis of non- bacteriologically confirmed TB, CXR has previously been recommended to be performed after a negative bacteriological test result and a trial treatment with broad spectrum antibiotics other than those used to treat TB (17, 18). However, trial treatment with broad spectrum antibiotics is not in line with general principles on the use of antibiotics, which should be reserved for treating a clear indication and not primarily used for diagnostic purposes. Trial treatment with antibiotics is particularly discouraged in children (22). Putting CXR at the end of a diagnostic algorithm may sometimes be the only option \u2013 for example in primary healthcare facilities where X-ray is not available and patients need to be referred to", "a secondary care facility. In this case, often patients with symptoms highly suggestive of TB and negative smear microscopy results are then referred to secondary care facilities for further evaluation with CXR. This approach is rational when infectious TB is the priority or if radiography access is limited. However, the approach can lead to delayed TB diagnosis and loss to follow-up during the diagnostic work-up, especially when a bacteriological test with low sensitivity is used, such as sputum-smear microscopy (which misses many true cases). One rationale for not doing a CXR before a bacteriological test is to avoid identifying a large group of people as possible TB patients via an early CXR, which can lead, in turn, to false-positive CXR-based clinical diagnosis of TB (see Sections 2.3.1 and 2.3.2, and Chapter 3). However, the risk of a false-positive clinical diagnosis can be reduced by using proper quality control as well as by improving access to sensitive and rapid molecular tests, or culture, or both, which can more effectively rule out TB than sputum-smear microscopy and can, therefore, reduce the number of cases diagnosed based on CXR findings. 2.3.4 Estimating the yield and cost to decide where to place chest X-ray in triaging for TB The judgement of whether to expand CXR use as part of triaging for TB and the decision of where to put CXR in a triaging algorithm need to be based on an assessment of the risks of overdiagnosis versus underdiagnosis, and in the context of resource demands, the availability of human resources, the accessibility of CXR, and the feasibility and cost effectiveness. It is also important to consider that if all tools included in a diagnostic algorithm are not located in the same physical location, patients risk being lost in the diagnostic pathway. A case study on CXR in TB detection algorithms in India is provided in box 3. It may be helpful to estimate for different triaging protocols the number of CXR investigations and number of bacteriological tests required (and related resource demands), as well as the potential yield (including true positives and false positives, and true negatives and false negatives; see Annex 1 for an example). Unfortunately, the scientific evidence about the performance and cost effectiveness of different triaging algorithms using CXR is limited. The ScreenTB tool (12), initially developed for systematic screening, can be used for preliminary modelling of the theoretical expected yield", "and related costs required for some triage algorithms and the epidemiological scenarios in a given setting. However, the assumptions (originally put in place for screening) may need to be changed, and the outputs of the tool are only indicative. The introduction of any new algorithm should be coupled with careful monitoring and evaluation of its performance, in terms of the yield and the proportion of detected cases that are bacteriologically confirmed (5).", "16 Chest radiography in tuberculosis detection BOX 3. Case study on chest radiography in the TB detection algorithms in India India has the highest TB burden of any country, representing 23% of the total global burden. Although policies requiring mandatory case notification, a new web-based information system and greater engagement with the private sector have led to significant recent increases in case notification, there is still a large case-detection gap. In response, the country is looking for ways to increase case detection, including developing more sensitive approaches for identifying persons who need to be evaluated for TB. CXR has, therefore, returned to the agenda after several decades of marginal programmatic use. CXR has long featured in TB detection in India, but its use has varied. In the 1960s, radiography was used for mass TB screening and clinical diagnosis of TB. These uses were accompanied by high rates of clinically diagnosed TB. Beginning in the 1990s, with the adoption of DOTS, CXR was still used to diagnose TB but less often because it was placed at the end of the recommended diagnostic algorithms, to be used only after multiple negative smear examinations and a trial course of antibiotics. Accordingly, the amount of training for providers dedicated to the use of CXR decreased substantially over the same period. When India launched its first national TB programme in 1962, District TB Officers were trained at the national level for 3 months. For more than 30 years, the main component of training aimed to help the officers develop skills in the CXR-based diagnosis of TB. After DOTS was introduced in the 1990s, under the Revised National TB Control Programme, training was gradually reduced to 2 weeks. The use of CXR was discouraged because previously TB had been overdiagnosed in the NTP when diagnosis was based on CXR. Consequently, the focus of training shifted to ensuring high-quality smear microscopy, and training in CXR vanished from the human resources development plan. Overall, this led to a decrease in the skills needed to evaluate CXRs, an inadequate infrastructure and availability of radiology, and minimal CXR monitoring and quality assurance, especially in peripheral areas. Throughout the period from the 1960s to the present, however, CXR has been widely used in the private sector, where it has been the preferred initial tool for TB detection, and it has also been used extensively for clinical diagnosis. No formal quality assurance", "procedures for CXR and clinical diagnosis in the private sector have been undertaken. In 2016, after programme evaluations suggested that only 5% of patients symptomatic for TB were screened completely using the existing diagnostic algorithms, and data from prevalence surveys suggested there would be an additional 30\u201340% diagnostic yield using CXR as a screening tool, the Ministry of Health and Family Welfare of India recommended revised diagnostic algorithms that feature CXR as an early triage tool for evaluating patients with suspected TB, to be used with bacteriological confirmatory evaluation and continued clinical assessment of bacteriologically negative patients. However, the implementation of the revised triage and diagnostic algorithms will likely be hampered by the limited availability of high-quality CXR. Currently, CXR technology is available only in the private sector and at the public sector referral level. Along with limited equipment for CXR, only limited personnel have been trained to deliver and interpret CXRs. Additionally, the financing for radiology services varies by state, and although many states have provisions for free-of-charge CXR in the general health budget for patients with suspected TB, some require fees from patients. T echnological innovations may provide future opportunities to address financial and human- resource capacity gaps in CXR access, including by using digital CXR in combination with telemedicine. More information can be found in the following resources: \u2022 International standards for tuberculosis care, third edition (20) \u2022 the website for the Practical approach to Lung Health (known as P AL) (29) \u2022 Xpert MTB/RIF policy update and implementation manual (2, 3) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23) \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Systematic screening for active tuberculosis: an operational guide (5) \u2022 ScreenTB tool: target prioritization and strategy selection for tuberculosis screening (12).", "17 Chest radiography in tuberculosis detection 3. CHEST X-RAY AS A DIAGNOSTIC AID 3.1 Chest X-ray as a diagnostic aid for respiratory and other intrathoracic diseases As discussed in Chapter 2, people with respiratory symptoms who are seeking care need to be evaluated not only for TB but for all relevant respiratory diseases, which may include, for example, non-TB infections, diseases of airflow obstruction (such as chronic obstructive pulmonary disease or asthma), neoplasms (such as lung cancer or pulmonary metastasis), occupational lung diseases (such as silicosis) or bronchiectasis. CXR is a useful diagnostic aid for several of these conditions, as well as for diseases that affect extrapulmonary intrathoracic structures (such as mediastinal lymph nodes, the pleura or pericardium). Good quality chest radiographs are essential for proper evaluation. CXR should be seen as a tool that can be used in comprehensive pathways for diagnosing respiratory and other intrathoracic diseases. Beyond algorithms for TB diagnosis and treatment, protocols are needed for the proper referral and management of other diseases, in line with the principles of the practical approach to lung health (29). CXR is an essential health technology that should be accessible to all. However, because access remains limited in many settings, and it may be available only in tertiary care, the choice to use CXR as a diagnostic aid clearly depends on the availability of and access to CXR (see Chapter 6). 3.2 Chest X-ray as a complement to bacteriological TB tests It must be underscored that although CXR is a useful adjunct in diagnosing TB, CXR alone cannot establish a diagnosis. Bacteriological confirmation of TB should always be attempted. The triage algorithms described in the previous chapter show only the steps leading to an initial bacteriological test, but not the subsequent bacteriological testing and clinical assessment that may be required. Additional bacteriological testing may be required after a negative initial bacteriological result. This is especially relevant if the initial test is sputum-smear microscopy, which has low sensitivity. For such patients, subsequent Xpert MTB/RIF testing or culture should be done if the clinical suspicion of TB is moderate to high \u2013 for example, due to CXR findings consistent with TB. Although Xpert MTB/RIF testing is more sensitive than smear microscopy, the sensitivity of the test in a given setting depends on the prevalence of smear-negative TB in the patient population; this is because the Xpert MTB/RIF assay is highly sensitive for", "smear-positive TB but only moderately sensitive for TB that is smear negative (2). Hence, repeated testing should be considered using the Xpert MTB/RIF assay or culture, or both, after an initially negative Xpert MTB/RIF assay or culture. Culture can improve the sensitivity of bacteriological confirmation, although it typically takes 6\u20138 weeks before results are available. Considerations for sequential bacteriological testing and suggested bacteriological test algorithms, including for diagnosing drug-resistant TB, are included in WHO\u2019s framework on implementing TB diagnostics as well as in the International standards for tuberculosis care (20, 33). Making a clinical diagnosis based on medical history (symptoms, TB exposure, risk markers), signs and CXR findings is sometimes reasonable in persons in whom TB cannot be ruled out despite negative bacteriological tests. In combination with clinical assessment, CXR may provide important circumstantial evidence for clinical diagnosis (20). Repeated CXR examination after a period of time could be considered, as interpretation of image changes could aid in clinical evaluation for TB and other diagnoses. Clinical diagnosis is particularly relevant in certain groups for whom it can be difficult to confirm a TB diagnosis with a bacteriological test. This includes patients for whom bacteriological tests tend to have lower sensitivity, such as people living with HIV or people with other immune-compromising conditions. It also includes patients from whom it is difficult to collect samples for bacteriological confirmation, such as young children. Moreover, for seriously ill patients (particularly persons with HIV infection), a clinical decision to start treatment often must be made without waiting for test results. Such patients may die if appropriate treatment is not begun promptly (4, 20, 23). In such patients, CXR can be particularly useful", "18 Chest radiography in tuberculosis detection as a diagnostic aid given the rapidity with which it delivers results. The risks associated with a delayed or missed TB diagnosis in these groups can be higher than the risks associated with a possible false-positive clinical diagnosis, which means that a clinical diagnosis made with a relatively low positive predictive value may be acceptable. However, it should be noted that the accuracy of CXR in these groups may be lower than in other groups. If a patient is not critically ill, follow-up bacteriological testing, repeat CXR and re- evaluation of TB and differential diagnoses should be considered (19, 20). Patients in whom a clinical diagnosis of TB has been made should be followed closely to ensure that a non-TB disease has not been misdiagnosed and left untreated. Follow-up should include repeat clinical and radiological assessment. For those who deteriorate or fail to improve, repeat bacteriological testing for TB should be considered (that is, to ensure the initial results were not falsely negative) and also diagnostic testing for non-TB diseases. Quality assurance for clinical TB diagnoses is important (see Chapter 5), both to not miss TB cases and to avoid overdiagnosis. Unnecessary TB treatment should be avoided to protect patients from harm and avoid wasting resources, both for patients and society. Moreover, making a false-positive clinical TB diagnosis when the illness has another cause can delay proper diagnosis and treatment of the true illness \u2013 for example, lung cancer (34). When an abnormality is present on CXR it is important to consider all possible differential diagnoses. Persons with confirmed or unconfirmed TB may have other concurrent lung conditions. Quality assurance involves ensuring high-quality CXR as well as high-quality CXR reading (35), (36). Quality and standardization can be improved by conducting multidisciplinary clinical rounds, convening groups of diagnostic experts and implementing peer review procedures. Monitoring and evaluation are essential. A useful indirect indicator of quality is the proportion of TB cases that have not been bacteriologically confirmed. A high proportion of clinically diagnosed TB may indicate overdiagnosis. A low proportion may indicate underdiagnosis. However, there is no established benchmark for the appropriate proportion of cases of bacteriologically confirmed TB. 3.3 Chest X-ray as part of a comprehensive diagnostic pathway in children CXR is useful in the diagnostic evaluation of TB as well as other intrathoracic diseases in children, especially younger children, in whom bacteriological evaluation", "is commonly negative. It should be part of a comprehensive diagnostic pathway that includes multiple steps, beginning with clinical assessment, the assessment of risk factors and exposure history, and CXR and bacteriological tests, as required. In most cases, children with TB have radiographic changes suggestive of TB (22). Adolescent patients with TB have radiographic changes similar to those seen in adult patients. Good-quality CXRs are essential for proper evaluation (22). A lateral CXR view may be required, especially in younger children and when bacteriological confirmation is challenging. For example, children younger than 4 years are more likely to have primary TB, and a lateral view will be important in identifying mediastinal or hilar lymphadenopathy (37). Details are provided in the Guidance for national tuberculosis programmes on the management of tuberculosis in children (22). As with adults, there are no specific features on clinical examination that can confirm that the presenting symptoms are due to TB. Every effort should be made to confirm the diagnosis of TB in a child using whatever specimens and laboratory tests are available (22). The Xpert MTB/RIF assay should be used as the initial test in all children suspected of having TB, regardless of their HIV status (2). It should be noted that children living with HIV have a substantially elevated risk of TB. The approach to diagnosing TB in children living with HIV is essentially the same as for diagnosis in HIV-negative children. However, this approach can be more challenging in children living with HIV because there is a high incidence of acute and chronic lung diseases other than TB; because children with HIV may have lung disease of more than one cause (multimorbidity), which can mask their response to therapy; and because there is an overlap of radiographic findings in TB and from other HIV-related lung diseases, making CXR less specific for detecting TB in children with HIV (22). CXR quality assurance can be especially challenging when CXR is used in children. Radiographers and medical staff require special training on taking and reading CXRs in children, and ensuring this training", "19 Chest radiography in tuberculosis detection occurs is a particular challenge in low- and middle-income countries where there are few paediatric- orientated radiologists. More information can be found in the following resources: \u2022 International standards for tuberculosis care, third edition (20) \u2022 Guidance for national tuberculosis programmes on the management of tuberculosis in children, second edition (22) \u2022 Xpert MTB/RIF policy update and implementation manual (2, 3) \u2022 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection (23).", "20 Chest radiography in tuberculosis detection 4. CHEST X -RAY AS A SCREENING TOOL FOR PULMONARY TB 4.1 Chest X-ray as a sensitive tool for screening for active TB Systematic screening for active pulmonary TB is defined as the \u201csystematic identification of people with suspected active TB in a predetermined target group, using tests, examinations or other procedures that can be applied rapidly\u201d (4). Unlike the evaluation of those who actively seek care for respiratory symptoms (see triaging, Chapter 2), the systematic screening of individuals for TB is typically initiated by a provider and offered in a systematic way to an apparently healthy target group that has been determined to have a high risk of TB. Systematic screening implemented within health facilities is a special systematic screening situation in which specific risk groups at high risk of TB are targeted for screening among people seeking care in health facilities \u2013 for example, people being treated for diabetes or people living with HIV who are attending a clinic to receive antiretroviral therapy. Systematic screening of all people seeking care in an outpatient department may be considered in a setting where TB is highly endemic. Such an approach can also be seen as aggressive triaging for TB; the same principles for choosing an appropriate screening algorithm apply. Systematic screening outside health facilities \u2013 such as in the community or in special institutions such as prisons or shelters for homeless people \u2013 is often labelled active case finding, which refers to a provider- initiated approach that actively reaches outside the health services. Such screening can help find prevalent cases of TB in the community that might otherwise go undiagnosed and untreated. It often requires screening a large number of people who do not have TB. Costs can be high, and the risk of a false- positive diagnosis is high when TB prevalence in the screened group is low or moderate (4). Because of this, choosing an accurate screening algorithm is critical, and there are specific considerations involved, including how well the screening and diagnostic tools perform in the population to be screened, the trade- off between risks and benefits to the person being screened, the ability of the screening algorithms to detect TB without risking overdiagnosis, and the feasibility and costs (4, 5). WHO\u2019s guideline Systematic screening for active tuberculosis: principles and recommendations describes 10 algorithms for screening for TB (4). Eight options", "include a symptom screen as the initial test (screening either for cough lasting longer than 2 weeks, or screening for any symptom consistent with pulmonary TB, including cough of any duration, haemoptysis, weight loss, fever or night sweats), and two options use CXR as the initial screening test. If symptom screening is used initially, then CXR can be used as a second screen to improve the pre-test probability of the subsequent diagnostic test and to reduce the number of people who need to undergo further diagnostic evaluation. See box 4 for an example of the use of CXR as a tool for TB screening in migrants and refugees. As discussed in Chapter 2, symptom screening has a low sensitivity, especially for detecting TB early, which is a primary objective of systematic screening. Nevertheless, symptom screening is a low-cost and feasible approach that may be the only option in some situations. CXR, however, is a good screening tool for pulmonary TB because of its high sensitivity (87% to 98%, depending on how the CXR is interpreted) (4), meaning that up to 98% of those with culture-positive TB who undergo CXR will have an abnormal result. From the perspective of the person being screened, CXR is a valuable tool because it provides rapid screening results for a range of medical conditions beyond TB (21). Like symptom screening, CXR has low specificity in an active case-finding situation (46% to 89%, depending on how it is read) (4), meaning that a significant proportion of individuals without TB will have an abnormal test result. This is due, in part, to the fact that CXR identifies many types of lung abnormalities, whether due to TB or to other lung conditions. For this reason, CXR should be used with a bacteriological confirmatory test that has high sensitivity and specificity for TB. However, as discussed in Chapter 2, it is unavoidable that some proportion of persons who screen positive by CXR and who are negative by bacteriological tests will be diagnosed based on CXR and clinical criteria alone. Such patients should be periodically re-evaluated to assess response to treatment for TB and to exclude other diseases that might explain the", "21 Chest radiography in tuberculosis detection radiographic findings. A significant proportion of those with a clinical diagnosis may not, in fact, have TB and, thus, may be treated unnecessarily. At the same time, some of the true TB cases will be missed. The proportions of false-positive and false-negative cases found through screening will depend on the TB prevalence in the screened group, on the quality of the laboratory test, and on the rigour used in making clinical diagnoses, including the quality of CXR and CXR reading, as well as the quality of clinical evaluation (4). It is essential to ensure that the diagnostic quality is high, including for clinical diagnosis. It is also important that people invited for screening are well informed about the diagnostic challenges. This is particularly important in the context of screening as compared with triaging, for two reasons: screening is normally provider-initiated rather than patient-initiated (which leads to particular ethical considerations) and the prevalence of TB in the tested group tends to be much lower (which leads to lower positive predictive values). Although CXR is the preferred screening tool from the viewpoint of test accuracy, it can be expensive and logistically challenging to use, especially during active case finding when screening is done as an outreach activity outside the health services. The best choice of screening tool for any given situation depends on several factors, including the setting where screening is to be done, the populations to be screened and their epidemiology of TB and associated risk factors, the resources available (such as, human or financial), and the feasibility of various screening options. CXR is a good choice in most screening scenarios, particularly those based in the healthcare setting (see Case study 2) or where it is feasible to utilize mobile X-ray technology, but it will not be feasible in some scenarios. WHO\u2019s Systematic screening for active tuberculosis: an operational guide provides some guidance for the processes of planning screening and choosing an appropriate screening approach (5). The operational guide (5) and the ScreenTB tool (12) can be used to model the potential yield of true-positive and false-positive cases from various screening approaches, as well as costs, which can help in prioritizing the risk groups to be screened and choosing a screening algorithm. As with the discussion of optimizing triage algorithms in section 2.3, the introduction of any new algorithm for screening should be coupled with", "22 Chest radiography in tuberculosis detection BOX 4. Case study on the International Organization for Migration\u2019s experience of using digital chest radiography and teleradiology to screen migrants for TB. The International Organization for Migration (IOM) conducts health assessments for selected immigrants and refugees during the process of resettlement. A key component of the health assessment is radiological screening for TB for migrants from countries with a significant burden of TB. CXR is performed on all adults and on children with indications for TB evaluation (such as a positive tuberculin skin test or interferon-gamma release assay, or being a close contact of a person with TB or HIV). For the detection of TB, an abnormal CXR suggestive of TB is the main criterion for referral for sputum-smear microscopy and culture examination; clinical suspicion is the main criterion for referral for cases with a normal CXR. Because this health screening is conducted in an apparently healthy population, TB is usually detected during an early phase of disease, and the findings on CXR are often subtle. Skilled radiologists experienced in interpreting screening CXRs for TB are essential. The difficulty in finding appropriately skilled radiologists, especially in rural areas, prompted the IOM to develop a Global T eleradiology and Quality Control Centre in 2012. The aim was to standardize and optimize the quality of CXR used across all IOM health assessments. The centre utilizes a teleradiology system, with web-based applications and live chat for communications and to transfer digital images and provide CXR reports in real time. The centre provides primary CXR reading if necessary, with a turnaround time of 1 hour, as well as quality control and radiology-related technical support to IOM health-assessment field operations globally. From 2011 to 2015, IOM conducted health assessments for more than 1.5 million people, of which 1.2 million immigrants and refugees were screened for TB using CXR as part of their health assessment. Among those screened, 5% had CXR findings consistent with TB, and among those almost 7% were diagnosed with TB. Among diagnosed TB cases, 84% were bacteriologically confirmed. The majority were culture-confirmed smear-negative cases. These experiences demonstrate the potential for using CXR to screen a large group of apparently healthy individuals for TB and find a significant number of cases. The high proportion of culture-confirmed smear- negative TB indicates the low sensitivity of smear microscopy and that it is possible to maintain a high standard", "of bacteriological confirmation with culture. The IOM experience also shows the potential for digital and communication technologies to increase access to CXR and to skilled radiology services globally. However, nearly 400 immigrants or 164 refugees needed to be screened to detect 1 case of TB. The cost effectiveness of this type of mass screening needs to be considered. The TB detection rate was 2.5 times higher in refugees than in immigrants, which indicates that screening targeted high-risk groups will be more cost-effective than screening all migrants. 4.2 Chest X-ray screening in TB prevalence surveys In the specific context of a national TB prevalence survey, in which a country\u2019s entire adult population is sampled and tested to determine the population prevalence of TB, screening is applied to identify individuals who should undergo bacteriological examinations. CXR is the most sensitive screening tool for identifying those survey participants with a high probability of having TB. For diagnosis, combining CXR and symptom checklists for screening (with, typically, a positive result in either category being sufficient to warrant further testing) with culture or an alternative bacteriological test with high sensitivity (such as the Xpert MTB/RIF assay), will generate the most accurate prevalence estimate for bacteriologically positive TB (which is the objective a TB prevalence survey). CXR should, therefore, be used for all participants in a survey, regardless of their symptoms or risk markers (21). It should be noted that prevalence surveys Total of 1 204 569 screened for TB with CXR: 836 462 immigrants and 368 107 refugees 63 884 (5.3%) had findings suggestive of TB: 30 172 (4%) immigrants and 33 712 (9%) refugees 4 341 (6.8%) diagnosed with TB: 2 096 immigrants and 2 245 refugees 84% laboratory confirmed (40% through smear, 60% through culture)", "23 Chest radiography in tuberculosis detection generally do not include children (usually defined as less than 15 years of age), due to ethical concerns and because they require distinct screening and diagnostic procedures, so survey findings do not represent the entire population and cannot be extrapolated to the younger age group. The screening strategy recommended by the WHO Global T ask Force on TB Impact Measurement is shown in Fig. 3. Those persons with abnormalities on CXR and/or found to have TB-compatible symptoms during the questionnaire screening are eligible for sputum examination with the Xpert MTB/RIF assay or culture, or both. Those who do not have abnormalities or symptoms suggestive of TB during screening are not eligible for bacteriological testing and do not submit sputum samples. For more information, see T uberculosis prevalence surveys: a handbook (21). FIG. 3. WHO\u2019s recommended screening strategy for TB prevalence surveys (21) CXR: chest X-ray. A screening strategy using symptom screening without CXR screening is not recommended because it will underestimate the true prevalence of TB. Between 23% and 70% of bacteriologically positive cases detected in recent surveys had chronic cough, meaning that, on average, half of bacteriologically confirmed cases will be missed by symptom screening alone (see Annex 2) (21). T o increase sensitivity, intentional overreading of CXRs should be encouraged in the context of a prevalence survey. That is, participants with any lung abnormality (even if it may not be considered typical of TB) should be referred for bacteriological examination. Overreading should ensure that almost all potential TB cases are referred for sputum examination. Because TB in an immunocompromised person with a high risk of TB, such as an HIV-positive individual or, to a lesser extent, a person with diabetes, often shows atypical manifestations in a CXR, using CXR abnormalities suggestive of TB to identify individuals eligible for sputum examination may not be sensitive enough. Therefore, the recommended definition for screening is any CXR abnormality in the lung (21). Follow-up of participants with abnormal CXR and negative bacteriological exams is sometimes warranted. ABNORMAL CXR and/or POSITIVE SYMPTON SCREEN NO BACTERIOLOGICAL TESTING BACTERIOLOGICAL TESTING Microscopy culture, Xpert MTB RFI YES NO", "24 Chest radiography in tuberculosis detection 4.3 Chest X-ray to rule out active TB before treating latent infection Due to the crucial importance of excluding active TB before initiating treatment for latent TB infection (LTBI), one of WHO\u2019s recommendations for managing LTBI in resource-rich settings with a TB incidence of < 100 cases/100 000 population states that before initiating treatment for LTBI, individuals should both be asked about any symptoms of TB and should undergo CXR. Individuals with TB symptoms or any radiological abnormality should be investigated further for active TB and other conditions. For more information, see the Guidelines on the management of latent tuberculosis infection (24). Guidelines for managing LTBI in resource-poor high-burden settings are being developed; presently, in such settings CXR is not usually used for evaluating asymptomatic children under 5 years of age. Using the combination of any abnormality in a CXR and/or the presence of any symptoms suggestive of TB (that is, any one of cough, haemoptysis, fever, night sweats, weight loss, chest pain, shortness of breath or fatigue) offers the highest sensitivity and negative predictive value for ruling out TB (24). More information can be found in the following resources: \u2022 Systematic screening for active tuberculosis: principles and recommendations (4) \u2022 Systematic screening for active tuberculosis: an operational guide (5) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 Guidelines on the management of latent tuberculosis infection (24) \u2022 Screening chest X -ray interpretations and radiographic techniques (10).", "25 Chest radiography in tuberculosis detection 5. TECHNICAL SPECIFICA TION, QUALITY ASSURANCE, QUALITY CONTROL, AND SAFETY 5.1 Technologies for chest X-ray and technical specifications WHO first specified a basic radiological system in 1975. The concept was developed further with a series of revisions. WHO\u2019s guiding principles in designing radiological units have been: \u2022 the radiological image must be high quality; \u2022 the equipment must be safe for patients and personnel; \u2022 the equipment must be easy to install and use; \u2022 required equipment maintenance should be minimal and quality assured; \u2022 if necessary , it must be possible to use the equipment with an unreliable electricity supply. T wo types of technology are used for CXR: analogue (that is, a system using film) or digital. It is important to highlight that both of these technologies employ the same principle of X-ray production (which is non-digital); the difference is the method of recording the result. In conventional systems, the result is recorded and displayed on an X-ray film but in digital systems, the result is recorded on a detector and displayed in a digital format on a computer screen (and it can also be printed on X-ray film or paper or sent to a digital device). Digital systems have several advantages over conventional systems. They reduce procedure time, have very low running costs (particularly when a hard copy image is not needed), save on staff requirements because the system is more user-friendly, produce superior image quality, give a lower radiation dose, allow for easier archiving and are more environmentally friendly. Moreover, they allow for telemedicine solutions and can be used for computer-aided reading. In 2000, WHO published the Consumer guide for the purchase of X-ray equipment (38), a comprehensive document that was aimed at small hospitals and large primary healthcare centres. The document covered not only technical specifications but also guidance on infrastructure, staffing and protection from radiation. However, because affordable digital technologies were not widely available for resource-poor settings at the time, the guide recommended only conventional X-ray technology with a manual or automatic film processing and development system. In 2016, WHO developed technical specifications for the 61 essential medical devices needed by healthcare facilities (39). The specifications for digital imaging systems in that document should help countries procure appropriate equipment. It was compiled by WHO in collaboration with a working group of experts, and will be continually updated. Among", "the 61 devices, 6 diagnostic X-ray-related devices are included (as of 29 September 2016): \u2022 the stationary basic diagnostic X -ray system, digital; \u2022 the mobile basic diagnostic X -ray system, digital; \u2022 the stationary basic diagnostic X -ray system, analogue; \u2022 the mobile basic diagnostic X -ray system, analogue; \u2022 the darkroom automated X -ray film processor; and \u2022 the daylight automatic X -ray film processor. Basic radiography is an essential technology in primary care, such as at health centres and district hospitals. The basic radiography unit (the stationary digital diagnostic X-ray system) has much wider functions than CXR, such as to investigate trauma or gastrointestinal diseases and to perform interventions, such as thoracic intubation, and the fixation or manipulation of fractures and dislocations. Mobile digital basic X-ray systems that can provide radiology services outside the radiology unit, such as in an operating theatre or intensive care unit, are listed in WHO\u2019s 2016 technical specifications as the second unit of radiography needed for hospitals.", "26 Chest radiography in tuberculosis detection In some facilities it is appropriate to have a CXR-specific stationary unit. WHO\u2019s specifications for stationary digital CXR systems are not available, but will be developed by WHO and its partners. Moreover, WHO\u2019s guidelines on radiography are limited to medical facilities. WHO is developing specifications for portable X-ray units, which are already widely used in small medical facilities, for home care, in military and disaster relief operations, for systematic TB screening and for TB prevalence surveys. The WHO Global T ask Force on TB Impact Measurement strongly recommends that countries do not use fluoroscopy or mass miniature indirect radiography for TB screening because these require a higher radiation dose (21). Since 2009, all national TB prevalence surveys, without exception, have adopted direct CXR technology. 5.2 How to choose chest X-ray technology There are many factors to consider when choosing the appropriate X-ray equipment. \u2022 Settings: For frontline hospitals and health centres, a stationary basic digital diagnostic X-ray system should be considered for the first X-ray unit, as X-ray technology has many diagnostic uses beyond CXR. An X-ray unit used only for CXR could be installed in the radiology department when the demand for CXR is high. For field use, options include a stationary X-ray unit (either in an X-ray van or container) or a portable unit. The choice depends on the accessibility of field sites, a country\u2019s regulations, the climate (temperature) and the daily demand for CXR images. \u2022 Costs: Costs depend on several factors. It is useful to think about the entire lifetime of the equipment when considering costs. Different technologies have varying levels of initial investment and running costs (including requirements for consumables, operational costs and costs for maintenance and parts). Digital systems have a higher initial cost but often offer savings on consumables (particularly when a hard copy of the CXR image is not necessary) and human resources. \u2022 Duration of use: Although X-ray equipment is sometimes acquired for a specific purpose or activity, such as for a systematic screening campaign or a prevalence survey, it should be assumed that it will be used for a much longer time period and for other purposes. Therefore, its utility should be considered in terms of its general use. \u2022 Field conditions: If the equipment is to be used in the field, important factors to consider are portability and power requirements. \u2022 Personnel: It", "is important to consider whether skilled personnel will be available to conduct CXR examinations, read the results and maintain the equipment in the setting in which it will be used. \u2022 Radiation exposure: Although none of the options present dangerous levels of radiation, newer digital technologies provide lower exposure to radiation. \u2022 Throughput capacity: Digital systems are good for tasks with a heavy workload \u2013 such as a prevalence survey, hospital-based systematic screening or active case finding in the community \u2013 because they shorten the processing time. \u2022 Availability of maintenance: Particularly for digital equipment, ensuring maintenance after the initial 1-year warranty period can be difficult in countries where maintenance services are scarce. 5.3 Computer-aided detection of TB New technologies for analyzing the results of CXR evaluations are being developed, including computer- aided detection (CAD) software that can analyze digital CXR images for abnormalities and the likelihood of TB being present. Such technology could help reduce interreader variability and delays in reading radiographs when skilled personnel are scarce. As of 2016, WHO provides no recommendations on using CAD for TB. A systematic review of five peer reviewed articles published in 2016 concluded that the evidence of CAD\u2019s diagnostic accuracy is limited by the small number of studies of the single commercially available CAD software (CAD4TB, Delft Imaging Systems, Veenendaal, the Netherlands). There were also important methodological limitations to the studies and their findings had limited generalizability (40). T o determine whether WHO should initiate a process to develop guidelines on CAD, WHO commissioned an extended systematic review to evaluate", "27 Chest radiography in tuberculosis detection both published and unpublished studies assessing CAD as a tool for evaluating persons with suspected TB and for TB screening (41). The following PICO questions were formulated (PICO refers to population, intervention, comparator, outcome). 1. What is the diagnostic accuracy of CXR interpreted by CAD for detecting TB confirmed with culture or a molecular test? 2. Is the diagnostic accuracy of a CXR analyzed with CAD superior , inferior or equivalent to that of a CXR interpreted by a human reader for detecting TB confirmed by culture or a molecular test? The review stratified results by use-case: in triage use-case studies, CAD was used for evaluating persons with suspected TB (that is, persons seeking care for TB symptoms); in screening use-case studies, it was used to screen populations at risk that may not be seeking care. The review focused on CAD4TB, the only commercially available CAD program for TB. CAD4TB analyses a digital CXR and produces an abnormality score ranging from 0 to 100, with higher scores indicating greater likelihood of TB. A threshold score is the abnormality score below which TB is considered ruled out. For this to be a generalizable diagnostic test, one would predefine a threshold for each use-case. However, threshold scores are currently not preselected by the test developers. Studies were identified through four medical databases as well as the developer of CAD4TB software, projects supported by the Stop TB partnership and researchers in the field. Of the 542 identified citations and studies with unpublished data, 13 were included in the systematic review: 5 published peer reviewed papers, 4 published conference abstracts and 4 unpublished studies. Seven studies were triage use- case, and 6 were screening use-case, of which 6 and 3, respectively, had results that addressed the PICO questions. Results were considered in light of the potential for bias and applicability concerns, and assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) approach (http:// www.quadas.org). A number of important methodological limitations were identified for both use-cases during quality assessment. The main sources of concern about the potential for bias and limited applicability were the inappropriate exclusion of participants (particularly in screening use-case studies) and how the threshold scores had been operationalized, in particular the use of threshold scores that were not prespecified. Concerns about generalizability also arose from the use of non-commercially available versions of CAD4TB, and", "from training staff and evaluating the software for CXR within the same study population. Studies were not equally affected by these methodological limitations. Overall, reviewers found that few studies used CAD4TB the way it will be used in the field \u2013 that is, with the most up-to-date commercially available version, with a prespecified threshold score and without having undertaken a pilot study to determine which threshold score to use. Furthermore, there was limited or no information about the performance of CAD4TB in several subgroups of interest, including people living with HIV and different age groups, particularly for the screening use-case studies. Finally, data disaggregated by sex or smear status were not available. No pooling of data was done due to the methodological heterogeneity of the reviewed studies, as well as to the low number of studies for each version of CAD4TB. Across versions, the software achieved high sensitivity for both use-cases, but with variable specificity. The sensitivity and specificity of the human CXR readers whose performance was compared with that of CAD4TB were variable. In a number of studies, CAD4TB\u2019s threshold score was set to match either the sensitivity or specificity of the human readers, thus limiting the comparisons of accuracy that could be made between the software and human readers. The software\u2019s sensitivity was similar to that of human expert readers in the triage use-case, but it was less specific. Performance varied when compared with non- expert readers. For the screening use-case, data were insufficient to draw conclusions about performance compared with humans. Based on the findings of the extended systematic review, WHO has decided not to initiate a guideline development process at the present time. CAD can be used for TB detection for research, ideally following a protocol that contributes to the required evidence base for guideline development. For this purpose, WHO plans to further specify the desirable characteristics of CAD for TB and develop advice on key research questions and appropriate study designs that can address those questions. Broad questions that should be addressed include the following:", "28 Chest radiography in tuberculosis detection \u2022 what is the added value of CAD in different places in the diagnostic pathway? \u2022 what is the added value of CAD in different populations and settings? \u2022 what should be the threshold scores for different populations or settings? \u2022 what needs to happen if a patient is symptomatic and a CAD assessment is negative? And what needs to happen if a patient is symptomatic and the CAD assessment is positive but the microbiological test is negative? \u2022 what is the cost effectiveness of CAD compared with human readers, considering different payment models? \u2022 what operational or implementation challenges exist for ensuring equitable access? \u2022 what needs to be done with preliminarily CAD-positive patients? For example, when would a human reader be engaged for final interpretation/reporting in each use case? \u2022 how could CAD be used as an aid to human CXR readers rather than as a replacement? T wo possible research strategies have been identified to generate evidence for WHO to issue recommendations on using CAD4TB. When new evidence has been generated, WHO will assess whether a guideline process should start. In strategy 1, data from individual patients and digital images from the higher quality studies identified in the extended review would be analysed independently of the CAD4TB developers, using the latest version of the software and pooling the results using a meta-analysis of individual patient data. Although this could provide evidence of sufficient quality for the triage use-case, it would be inadequate for the screening test use-case. Hence, a complementary undertaking in strategy 1 would be to compile a standard panel of CXRs taken from existing databases, and use this panel to evaluate CAD4TB. Potential data sources include completed or ongoing studies that utilize digital CXR in either a triage or screening use-case and also use the required reference standard as defined but that are not utilizing CAD software (in order to avoid the developers having access to the files for software training), TB prevalence surveys and other existing data sets of digital CXR files with appropriate pathology reference standards. The timeline of this strategy is estimated to be 1 year, but it needs to be further clarified. Strategy 2 would involve identifying planned or ongoing trials of CAD, or undertaking new studies, and integrating an evaluation of CAD into that research. The main focus would be the screening use-case. Design", "considerations that would ensure studies are of sufficient quality would include using predefined threshold scores according to the use-case; enrolling important subgroups of patients (defined by sex, age, HIV status, smear status); using CAD for all participants (in triage studies, this would include testing all participants with the reference test; in screening studies, this would include testing at least a subset of asymptomatic persons with the reference test); and for comparison, having human readers who are blinded to CAD scores and microbiological data, and using standardized categories for reporting CXR results. The timeline for this strategy is estimated to be 2\u20133 years but depends on the ability to integrate an evaluation of CAD into planned studies and the availability of funding. 5.4 Quality assurance and quality control There are two major areas of quality assurance for CXR: the quality of CXR imaging and the quality of CXR reading. The quality of CXR imaging is associated with the quality of the hardware being used and the quality of the techniques and applications. WHO provides technical specifications for X-ray machines and the equipment related to handling X-ray films and images, as well as checklists and workbooks (http://www. who.int/diagnostic_imaging/publications/en/). The WHO manual of diagnostic imaging is available on the website of the International Society of Radiology (http://www.isradiology.org/isr/books_technique.php) (7). Also, the Handbook for district hospitals in resource constrained settings on quality assurance of chest radiography was developed specifically for TB programmes (35). Quality control of CXR reading is also essential. Underreading leads to missed opportunities for diagnosing and treating TB, and overreading leads to excess burdens on TB laboratories, as well as possible false-", "29 Chest radiography in tuberculosis detection positive clinical diagnoses (10). Another resource developed specifically for quality assurance in TB programmes in district hospitals is the Handbook for district hospitals in resource constrained settings for the quality improvement of chest X-ray reading in tuberculosis suspects (36). In addition to qualifications such as diplomas, masters\u2019 degrees and fellowships, several distance-learning or self-training opportunities are available for ensuring quality control standards. Additionally, some professional societies have developed educational materials, and some of these are listed at the end of this chapter. The International Commission on Radiology Education, part of the International Society of Radiology, provides its own educational materials as well as links to materials from other sources (11). Standardized CXR reporting forms and peer review, which may be accomplished by holding regular conferences in hospitals or at local TB diagnostic committees, can be useful for standardizing reading and interpretations. In systematic TB screening campaigns and TB prevalence surveys involving non-specialist screening physicians or clinical officers, a specialist often assesses the primary reading (in what is known as a central reading system). Comparing laboratory results with CXR results can help to improve the quality of radiological screening and diagnosis. Monitoring the proportion of clinically diagnosed cases out of all TB cases can serve as an indicator of diagnostic quality. However, WHO has not defined formal procedures for internal or external quality assessment of CXR interpretation for TB screening and detection. 5.5 Safety A proportion of the X-rays used in radiography are absorbed by the body. The potential effects from ionizing radiation depend on the dose. At doses much higher than those of typical diagnostic imaging exams, the damage may be extensive enough to affect tissue function, and the damage may become clinically observable (for example, as skin reddening or burns). Effects of this type are called tissue reactions or deterministic effects, and they occur only if the radiation dose exceeds a certain threshold (42). The long- term risks from ionizing radiation include an increased risk of cancer. Direct CXR is a safe technology using a radiation dose of 0.1 mSv, which corresponds to 1/30 of the average annual radiation dose from the environment (3 mSv) and 1/10 of the annual accepted dose of ionizing radiation for the general public (1 mSv). As a point of reference, the radiation dose of one CXR is equivalent to or less than the radiation exposure received during", "return travel on an intercontinental flight. Therefore, exposure to the low radiation doses delivered to patients during a CXR poses a small risk of inducing tissue reactions or cancer in the years to decades following the examination (43). However, it should be noted that a linear non-threshold relationship is assumed between radiation exposure and the risks of effects of this nature. Based on this linear model, the probability of developing cancer is presumed to increase even following exposure to low doses of radiation, although the increase in risk is extremely small. Even though the individual risk associated with radiation exposure from CXR is low, when a large number of individuals are exposed, the associated risks may still constitute a public health issue. Children and pregnant women are especially vulnerable to ionizing radiation. Also, children have a longer life expectancy, resulting in a larger window for developing long-term radiation-induced health effects. When imaging small children and infants, exposure parameters should be adjusted from those used for adults to avoid using a higher dose than necessary. Unnecessarily high doses and their associated risks can be substantially reduced without affecting image quality by customizing exposure settings to deliver the lowest radiation dose necessary for providing an image that is fit for the clinical purpose. For pregnant women and the fetus, a CXR does not pose any significant risk, provided that good practices are observed, as the primary beam is targeted away from the pelvis (21). Due to the potential risks, the decision to expose patients to radiation during imaging procedures must adhere to two overall principles of radiation protection in medicine: justification and optimization. Justification means that the need for medical imaging should be assessed by weighing the expected benefits against the potential radiation risk, taking into account the benefits and the risks of alternative techniques that do not involve exposure to radiation. The procedure should be judged to do more good than harm. Optimization in medical imaging refers to keeping doses as low as reasonably achievable to obtain a useful image. X-ray personnel should at all times ensure that the benefits of an examination outweigh the potential risks from radiation exposure and that the patient is exposed to as little radiation as possible (14, 44, 45).", "30 Chest radiography in tuberculosis detection Staff performing CXR must be familiar with protection measures for themselves, for patients and for others who may be exposed. Important concepts in radiation protection include consideration of the following areas: Type of exposure, including: \u2022 medical exposure (exposure of clients, such as patients and study participants); \u2022 occupational exposure; \u2022 public exposure. Place of exposure, including: \u2022 controlled areas, such as the X-ray room and areas directly connected to X-ray rooms (used by X-ray staff and assistants during the X-ray examinations); \u2022 supervised areas, such as areas in the vicinity of the X -ray room, which are usually part of the X-ray department. Protection measures, including: \u2022 shielding \u2013 that is, barriers of attenuating material around the radiation source, such as concrete walls and lead-containing panels, curtains and windows; \u2022 distance from the radiation source. Preventing exposure for staff and the general public is particularly important when X -ray systems are taken outside of medical facilities, such as during systematic screening using mobile CXR in the community. Tuberculosis prevalence surveys: a handbook provides advice on how to ensure safety in the field (21). When a van with a full size X-ray system with safety and power features appropriate for a hospital is available, the safety standards applied for health facilities can be used. When portable CXR units are placed in non-shielded areas, then restricted areas should be set up, clearly marked and monitored under the guidance of the radiological unit of the survey team. Radiometers and film badge dosimeters should be used, and rules should be devised for how to direct the X-ray beam. More information can be found in the following resources: \u2022 Radiation protection and safety of radiation sources: international basic safety standards, interim edition (46) \u2022 T uberculosis prevalence surveys: a handbook (21) \u2022 WHO\u2019s diagnostic imaging website (14) \u2022 WHO\u2019s Consumer guide for the purchase of X-ray equipment (38) \u2022 Handbook for district hospitals in resource constrained settings for the quality improvement of chest X -ray reading in tuberculosis suspects (36) \u2022 Handbook for district hospitals in resource constrained settings on quality assurance of chest radiography (35) \u2022 Communicating radiation risks in paediatric imaging (47) \u2022 International Commission on Radiology Education (42) \u2022 W orld Federation of Pediatric Imaging: TB resources (48) \u2022 Radiographic manifestations of tuberculosis: a primer for clinicians (9) \u2022 Screening chest X -ray interpretations and", "31 Chest radiography in tuberculosis detection 6. STRA TEGIC PLANNING FOR USING CHEST X-RAY IN NATIONAL TB CARE This chapter describes the strategic planning steps needed to introduce, expand, or systematize the use of CXR in TB care and prevention. Since CXR is not a TB-specific tool, developing a strategic plan for CXR should be done as a part of making general improvements to imaging services in the healthcare sector and within the broader framework of health-system strengthening and providing universal health coverage. This will increase the relevance and acceptance of investments in the technology and related capacity strengthening, and improve the overall efficiency and cost effectiveness of radiography services. Accordingly, the strategic planning process should involve all relevant stakeholders interested in introducing or expanding the use of CXR within the health sector. Including all stakeholders can be beneficial because different stakeholders will be able to utilize different sources of funding. However, this strategy may also be hampered by conflicting goals or expectations. If possible, the process needs to be integrated into the development of a national strategic plan for TB care, as well as into the broader national health plan. The level of integration will depend on the structure of the national health system and the level of decentralization in planning, as well as the timing of the strategic planning process at all levels. Strategic planning involves: 1. defining the objective of using CXR in the health system; 2. performing a situation analysis; 3. defining specific TB targets to which introducing, expanding or systematizing the use of CXR will contribute; 4. developing an operational plan, with a detailed budget and financing plan. Strategic planning for CXR should begin by defining the objective of using CXR within the health system and within the NTP national strategic plan \u2013 for example, it may be used to improve care for patients with respiratory diseases. Planning should then proceed by undertaking a situation analysis to understand the current state of and capacity for CXR in the country, the current epidemiology of TB and the possible contribution of CXR to TB care. T able 1 specifies the relevant questions that should be addressed by the situation analysis; the process should focus on those issues that are most relevant to the stated objective for current and planned use of CXR.", "32 Chest radiography in tuberculosis detection Area to assess Relevant issues to be addressed Potential information sources CXR capacity Determine the current state of CXR use in healthcare in the country, within both the public and the private sectors, including: \u2022 existing infrastructure, equipment (including specifications) and current workload and capacity; \u2022 existing human resources available to both conduct and read CXRs, and any available measures of their competencies; \u2022 existing internet connectivity capacity for e-health/telemedicine options, if applicable; \u2022 percentage of machines that are operational; \u2022 maintenance arrangements: how are maintenance issues reported and acted upon? What human resources and which budget (or budgets) are used for maintenance? \u2022 current financing: who pays for new equipment and for ongoing consumables, and from which budget (or budgets)? \u2022 what is the fee structure for end users, if any , in both the public and private sectors? \u2022 all stakeholders interested in using CXR and improving its use. Service availability and readiness assessment (known as SARA) surveys; national health insurance plans or other payment structures Determine existing national policies and regulations affecting the use of radiology , including: \u2022 its placement on the list of essential diagnostic services for the health service; \u2022 its placement on the list of essential medical devices; \u2022 quality assurance and quality control mechanisms; \u2022 safety policies and practices; \u2022 other existing national policies regarding the use of radiography , such as policies pertaining to health screening for immigrants or for occupational health screening. National guidelines on radiation safety; national screening policies for using CXR, such as to screen immigrants or for occupational health screening, or screening in prisons Map needs for human resources and capacity strengthening in the public and private sectors for introduction, scale up and quality assurance/quality control; consider: \u2022 radiologists and radiographers; \u2022 professional societies; \u2022 infrastructure for training and capacity strengthening; \u2022 capacity for e-health/telemedicine options. Professional societies that utilize CXR (such as radiologists and pulmonologists) Epidemiology of TB Determine the current epidemiology of TB in the region, including: \u2022 the geographical distribution of cases; \u2022 the age distribution of cases; \u2022 current case-detection gaps; \u2022 the current epidemiology of risk factors for TB; \u2022 any results from prevalence surveys or other research indicating the proportion of bacteriologically confirmed cases reporting no or vague symptoms of TB because this indicates the contribution that CXR could make to case detection; \u2022 CXR", "accuracy data from prevalence surveys or other research; \u2022 the profile of persons with suspected TB and where they would likely enter the health system, or how they could be detected through active case-finding initiatives (including children), as this will determine the current gap in CXR services and the potential workload of CXR. National TB surveillance data; WHO\u2019s global TB report; prevalence surveys; other relevant research findings from the country TB activities involving CXR Consider current and planned activities that require increased introduction or scale up of CXR and quality assurance in the country in terms of: \u2022 improving triaging; \u2022 improving the clinical diagnosis of TB; \u2022 improving the diagnosis of childhood TB; \u2022 implementing systematic screening in risk groups; \u2022 scaling up detection and treatment of latent TB infection. National strategic plan for TB; concept notes from the Global F und, or similar strategic planning for funding CXR: chest X-ray.", "33 Chest radiography in tuberculosis detection Based on the findings of the situation analysis, the TB control targets that CXR will contribute to need to be defined for its introduction, and for expanding or systematizing its use. For example, it should be specified whether the intended target is to increase case detection, rationalize the use of Xpert MTB/RIF testing or assist with the initiation of treatment for LTBI. Similarly, stakeholders not using CXR for TB should define their targets for introducing or expanding CXR use. The operationalization plan for integrating CXR into TB control should then be defined, beginning with the broader questions of CXR technology and placement in the healthcare system, and then using that information to proceed to address more detailed aspects of implementation, such as the following. \u2022 Where in the health system will CXR will be placed \u2013 for example, at the primary healthcare level, at the referral level, in hospitals, in mobile screening units? \u2022 Which CXR technology is best suited to the planned placement, or the desired improvement in the quality of existing CXR technology? This will be determined largely by the intended uses for CXR \u2013 for example, whether it will be used in routine care at primary healthcare centres or in a prevalence survey . \u2022 What additional infrastructure or equipment will be required, such as vans for mobile screening units or computers and internet connectivity for digital systems? \u2022 What is the approximate cost of such equipment, both in terms of procurement and ongoing operation and maintenance costs? Detailed budgeting comes later in the process (see below), but rough budget estimates are needed earlier to check that the proposed approaches are broadly affordable and cost effective. \u2022 What is the place of CXR in triaging, screening and diagnostic algorithms? What possible modifications could be made to current algorithms to make better use of CXR? \u2022 What is the expected increase in TB detection from the new algorithms or new placement of a CXR system? \u2022 What human resources are required for CXR use? \u2022 What are the initial training requirements and ongoing quality assurance requirements for CXR use? \u2022 Is there a need for technical assistance during the implementation of the operational plan? \u2022 What is the plan for monitoring and evaluating the use of CXR? \u2022 What is the plan for any operational research to be conducted in conjunction with", "CXR use in TB control? How will the associated data security and patient privacy issues be addressed? \u2022 What implementation steps are required to achieve the defined objectives and targets, and who will perform the steps and when? Along with this operational plan, a detailed budget needs to specify who will pay for the costs associated with using CXR, taking into account the different levels and budgeting processes of the entire health system. The budget should show the total cost of implementing and operationalizing CXR activities, the sources of funding and the funding gaps. The NTP , other departments of the ministry of health and other concerned ministries should work together to address the gaps in funding CXR for TB care to ensure the costs are not passed on to patients. Such costs can be catastrophic for individuals already facing severe economic and other stresses as a result of their illness. For more details, see WHO\u2019s Toolkit to develop a national strategic plan for TB prevention, care and control (49).", "34 Chest radiography in tuberculosis detection Annexes Annex 1. Yield and costs of triage algorithms in a hypothetical population of 100 000 with different TB prevalence levels The yields of true-positive, false-positive, true-negative and false-negative TB diagnoses (using liquid culture as the gold standard), and the cost per true case of TB detected, were modelled for different triage algorithms and different prevalence levels in a hypothetical population of 100 000 persons seeking healthcare. T able A1 displays the assumptions about test accuracy that are based on estimates from the systematic review done for the guideline on systematic screening for active TB (4). It should be noted that these estimates are from systematic screening studies (mainly TB prevalence surveys) and are likely to be different in a triage scenario. The reason for using these assumptions is that no data from systematic reviews are available for triage scenarios. The cost estimates are the same as the pre-set values on the ScreenTB tool. The ScreenTB tool (5, 12) can be used to model the yield and costs for these algorithms based on different assumptions. Table A1. Assumptions used to model the yield and costs per true case of TB detected Test Sensitivity Specificity Test costs a Operational costsa Cough screen 0.35 0.95 0 0.05 Any symptom screen 0.77 0.68 0 0.05 Digital chest X-ray 0.98 0.75 1.00 4.00 Sputum-smear microscopy 0.61 0.98 1.50 0.50 Xpert MTB/RIF assayb 0.92 0.99 10.00 7.00 a Costs are per person tested in US dollars. b Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). T able A2 displays the results of modelling with a TB prevalence of 250 cases per 100 000 population; T able A3 displays the results of modelling with a TB prevalence of 500 cases per 100 000 population; and T able A4 displays the results of modelling with a TB prevalence of 1 000 cases per 100 000 population.", "35 Chest radiography in tuberculosis detection Table A2. Yield and costs per true case of TB detected by triage algorithms in a hypothetical population of 100 000 with a TB prevalence of 250 cases/100 000a Algorithm True positive False positive False negative True negative Cost per case Number needed to screenb 1 (Prolonged cough SSM) 53 100 197 99 650 286 1 887 2 (Prolonged cough CXR SSM) 52 25 198 99 725 635 1 924 3 (Any symptom SSM) 117 638 133 99 112 592 855 4 (Any symptom CXR SSM) 115 160 135 99 590 1 582 870 5 (CXR SSM) 149 499 101 99 251 3 694 672 6 (Prolonged cough Xpert) 80 50 170 99 700 1 141 1 250 7 (Prolonged cough CXR Xpert) 79 12 171 99 738 671 1 266 8 (Any symptom Xpert) 177 319 73 99 431 3 112 565 9 (Any symptom CXR Xpert) 174 80 76 99 670 1 750 575 10 (CXR Xpert) 225 249 25 99 501 4 125 445 CXR: chest X-ray; SSM: sputum-smear microscopy; Xpert: Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). a The algorithms are described in detail in Chapter 2. b This is the number needed to screen to detect one true case. Table A3. Yield and costs per true case of TB detected by triage algorithms in a hypothetical population of 100 000 with a TB prevalence of 500 cases/100 000 a Algorithm True positive False positive False negative True negative Cost per case Number needed to screenb 1 (Prolonged cough SSM) 107 100 393 99 400 143 935 2 (Prolonged cough CXR SSM) 105 25 395 99 475 320 953 3 (Any symptom SSM) 235 637 265 98 863 296 426 4 (Any symptom CXR SSM) 230 159 270 99 341 795 435 5 (CXR SSM) 299 498 201 99 002 1 842 335 6 (Prolonged cough Xpert) 161 50 339 99 450 575 622 7 (Prolonged cough CXR Xpert) 158 12 342 99 488 347 633 8 (Any symptom Xpert) 354 318 146 99 182 1 562 283 9 (Any symptom CXR Xpert) 347 80 153 99 420 887 289 10 (CXR Xpert) 451 249 49 99 251 2 065 222 CXR: chest X-ray; SSM: sputum-smear microscopy; Xpert: Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). a The algorithms are described in detail in Chapter 2. b This is", "36 Chest radiography in tuberculosis detection Table A4. Yield and costs per true case of TB detected by triage algorithms in a hypothetical population of 100 000 with a TB prevalence of 1 000 cases/100 000a Algorithm True positive False positive False negative True negative Cost per case Number needed to screenb 1 (Prolonged cough SSM) 214 99 786 98 901 73 468 2 (Prolonged cough CXR SSM) 209 25 791 98 975 166 479 3 (Any symptom SSM) 470 634 530 98 366 149 213 4 (Any symptom CXR SSM) 460 158 540 98 842 401 218 5 (CXR SSM) 598 495 402 98 505 922 168 6 (Prolonged cough Xpert) 322 50 678 98 950 295 311 7 (Prolonged cough CXR Xpert) 316 12 684 98 988 185 317 8 (Any symptom Xpert) 708 317 292 98 683 786 142 9 (Any symptom CXR Xpert) 694 79 306 98 921 453 145 10 (CXR Xpert) 902 248 98 98 752 1 039 111 CXR: chest X-ray; SSM: sputum-smear microscopy; Xpert: Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, United States). a The algorithms are described in detail in Chapter 2. b This is the number needed to screen to detect one true case.", "37 Chest radiography in tuberculosis detection Annex 2. Proportion of TB cases detectable through screening with chest X-ray or by screening for chronic cough The results of several recent prevalence surveys are presented below (T able B1), including the proportion of TB cases identified that reported various TB symptoms and that had abnormal CXR results. In particular, the column \u201cPercentage positive only by CXR\u201d demonstrates the potential contribution of CXR to TB detection over screening or triage based on symptoms alone. Table B1. Proportion of TB cases detectable through screening with chest X-ray or by screening for chronic cough among persons diagnosed with bacteriologically confirmed TB in recent TB prevalence surveys a Country No. of bacteriologically confirmed cases No. symptom positive, CXR positive No. symptom positive, CXR negative No. symptom negative, CXR positive Percentage positive by both CXR and symptoms Percentage positive only by CXR Percentage positive only by symptoms Cambodia 314 90 3 216 29 69 1 Ethiopia 110 45 12 53 41 48 11 Gambia 77 32 12 33 42 43 16 Ghana 202 67 15 85 33 42 7 Indonesia 426 220 25 181 52 42 6 Laos 237 111 7 119 47 50 3 Malawi 132 25 67 40 19 30 51 Mongolia 248 44 7 190 18 77 3 Myanmar 311 65 1 231 21 74 0 Nigeria 144 76 16 52 53 36 11 Pakistan 341 157 40 142 46 42 12 Rwanda 40 15 4 21 38 53 10 Sudan 112 44 8 43 39 38 7 Thailand 142 42 6 94 30 66 4 Uganda 160 63 16 81 39 51 10 Zambia 265 115 46 104 43 39 17 Zimbabwe 107 29 10 64 27 60 9 CXR: chest X-ray. a Data from country prevalence surveys or personal communication. 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The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers\u2019 products does", "not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distin - guished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Designed by minimum graphics Cover design by Irwin Law", "iii iii Contents Acknowledgements vii Abbreviations xiii 1. Introduction 1 2. Global TB commitments, strategy and targets 3 3. Main findings and messages 6 4. Conclusions 38 References 39 Annex 1. Basic facts about TB 43 Annex 2. Data sources and access 45 Annex 3. WHO global lists of high TB burden countries 47 Annex 4. Updates to estimates of TB disease burden 53 Annex 5. The WHO TB-SDG monitoring framework 56", "Dr Tedros Adhanom Ghebreyesus Director-General World Health Organization This is a crucial period. Even as we must strive to meet the commitments from the second United Nations high-level meeting on TB, we have entered a new period of scarcity. WHO is committed to working with donors, partners and affected countries to mitigate the impact of funding cuts, find innovative solutions, and mobilize the political and financial commitments needed to End TB.", "v Dr Tereza Kasaeva Director Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections WHO\u2019s Global tuberculosis report 2025 shows that progress is possible, even in the face of persistent challenges. Coverage of TB prevention, diagnosis, and care continues to expand, powered by new WHO-recommended tools, from AI-driven screening and rapid diagnostics to shorter, more effective treatments to save lives. WHO is leading the charge, providing technical expertise and driving innovation, to ensure equitable access to these innovations for everyone, everywhere.", "vii Acknowledgements TB/HIV dataset. Review and validation of TB/HIV data were undertaken by WHO staff in collaboration with Vic- toria Bendaud (UNAIDS). Juliana Daher and Mary Mahy (UNAIDS) provided epidemiological data that were used to estimate TB incidence and mortality among people with HIV. The main text of the report was written by Katherine Floyd, with contributions from Mathieu Bastard, Dennis Falzon, Tereza Kasaeva, Irwin Law and Takuya Yamana - ka. Irwin Law organized the preparation of all figures and tables, which were produced by Mathieu Bastard, Nebiat Gebreselassie, Irwin Law, Hazim Timimi and Takuya Yamanaka. Annexes 1 and 5 were prepared by Katherine Floyd; Annex 2 by Hazim Timimi; Annex 3 by Katherine Floyd and Irwin Law; and Annex 4 by Mathieu Bastard, with contributions from Nimalan Arinaminpa - thy and Katherine Floyd. The report webpages on TB incidence and mor - tality were prepared by Nimalan Arinaminpathy, Mathieu Bastard and Katherine Floyd. The webpage on drug-resistant TB was prepared by Mathieu Bastard. The webpage on national TB prevalence surveys was prepared by Irwin Law. The webpages on TB diagnosis and treatment were prepared by Katherine Floyd and Takuya Yamanaka, with contributions from Patricia Hall-Eidson, Alexei Korobitsyn, Fuad Mirzayev, Carl-Mi - chael Nathanson and Linh Nhat Nguyen. The webpage on TB prevention and screening was prepared by Anna - bel Baddeley, Dennis Falzon, Avinash Kanchar, Cecily Miller and Hazim Timimi. The webpages on financing for TB prevention, diagnostic and treatment services were prepared by Taghreed Adam and Takuya Yamanaka, with contributions from Katherine Floyd. The webpages on universal health coverage (UHC) and TB determi - nants were prepared by Mathieu Bastard. The webpage on national surveys of costs faced by TB-affected house- holds, social protection and human rights was prepared by Takuya Yamanaka, with contributions from Taghreed Adam, Katherine Floyd and Monique Kamphuis. The webpage on multisectoral accountability was prepared by Hannah Monica Dias, Anna Stukalova, Yi Wang and Takuya Yamanaka. The webpage on TB research and innovation was prepared by Nebiat Gebreselassie and Irwin Law, with contributions from Dennis Falzon, Kath- erine Floyd, Medea Gegia, Patricia Hall-Eidson, Avinash Kanchar, Alexei Korobitsyn, Cecily Miller, Fuad Mirzayev and Matteo Zignol. Support for data analysis and asso - The Global tuberculosis report 2025 was produced by the WHO Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections. The core report team included Taghreed Adam, Nimalan Arinamin - pathy, Annabel Baddeley, Mathieu", "Bastard, Dennis Falzon, Katherine Floyd, Nebiat Gebreselassie, Avinash Kanchar, Irwin Law, Cecily Miller, Hazim Timimi, Yi Wang and Takuya Yamanaka. This team was led by Katherine Floyd. Overall oversight was provided by the Director of the Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections, Tereza Kasaeva. The data collection form was developed by Hazim Timimi, with inputs from staff from across the WHO Department for HIV, Tuberculosis, Hepatitis and Sex - ually Transmitted Infections. Hazim Timimi led and organized all aspects of data and code management, including the preparation and implementation of the web system used for the 2025 round of global tubercu - losis (TB) data collection from 215 countries and areas. Data were reviewed by the following staff at WHO headquarters: Annabel Baddeley, Mathieu Bastard, Annemieke Brands, Hannah Monica Dias, Dennis Falzon, Medea Gegia, Lic\u00e9 Gonzalez Angulo, Patricia Hall-Eidson, Monique Kamphuis, Avinash Kanchar, Alexei Korobit - syn, Marek Lalli, Cecily Miller, Carl-Michael Nathanson, Linh Nguyen, Gita Parwati, Debora Pedrazzoli, Samuel Schumacher, Lana Syed, Hazim Timimi, Sabine Verkuijl, Kerri Viney, Elena Vovc and Yi Wang. Data for the Euro - pean Region were collected and validated jointly by the WHO Regional Office for Europe and the European Cen - tre for Disease Prevention and Control (ECDC). Peter Dodd (University of Sheffield, United Kingdom of Great Britain and Northern Ireland) made key con - tributions to the production of estimates of TB disease burden disaggregated by age and sex and estimates of the disease burden caused by drug-resistant TB. Andrew Siroka (Data Driven) contributed to the review of financing data and Mikashmi Kohli (WHO consultant) contributed to the review of data related to TB diagnos- tic testing. Doris Ma Fat from the WHO Mortality and Burden of Disease team provided data from the WHO mortali - ty database that were used to estimate the number of deaths caused by TB among HIV-negative people. The joint United Nations Programme on HIV/AIDS (UNAIDS) managed the process of data collection from national HIV programmes and provided access to their", "viii Global tuberculosis report 2025 ciated preparation of report webpage content was provided by Glocal Commune LLC; the report team is very appreciative of their excellent work. The featured topic about the 2023 national TB prev - alence survey in Cambodia was prepared by Nimalan Arinaminapathy and Irwin Law, with contributions from Katherine Floyd and in close collaboration with the Min- istry of Health and the WHO Country Office in Cambodia. Particular thanks are due to Mao Tan Eang (Ministry of Health), Huot Chan Yuda (National Centre for Tubercu - losis and Leprosy Control, Cambodia), Ikushi Onozaki (Research Institute of Tuberculosis/Japan Anti-Tuber - culosis Association, Japan), Khay Mar Aung (Research Institute of Tuberculosis/Japan Anti-Tuberculosis Asso - ciation, Japan) and Serongkea Deng (WHO Country Office, Cambodia). The featured topic about the impact of 2025 cuts to international donor funding for TB on TB services was prepared by Nimalan Arinaminpathy, Kath- erine Floyd and Irwin Law, in close collaboration with Karina Halle (WHO Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections), Clarissa Halum (WHO Country Office, the Philippines), Thom - as Hiatt (WHO Country Office, the Philippines), Nebiat Gebreselassie, Taye Letta Janfa (Ministry of Health, Ethiopia), Setiawan Laksono (WHO Country Office, Indo- nesia), Nkateko Mkhondo (WHO Country Office, South Africa), Angel Mubanga (National TB Programme, Zam - bia) and Sabine Verkuijl. The featured topic about the expansion of TB preventive treatment in China was pre - pared by Zhongdan Chen (WHO Country Office, China), Dennis Falzon and Yi Wang, in close collaboration with Yanlin Zhao and Caihong Xu (Center for Disease Control and Prevention, China) and Limei Zhu (Jiangsu Munic - ipal Disease Control and Prevention Center, China). The featured topic about TB and gender was prepared by Nimalan Arinaminpathy, Mathieu Bastard, Stephen Bertel Squire (Liverpool School of Tropical Medicine, United Kingdom of Great Britain and Northern Ireland) and Katherine Horton (London School of Hygiene and Tropical Medicine, United Kingdom of Great Britain and Northern Ireland). The online technical appendix that explains the methods used to produce estimates of TB disease burden was prepared by Mathieu Bastard, with contri - butions from Nimalan Arinaminpathy and Peter Dodd. The online technical appendix that explains the meth - ods used to produce estimates related to TB financing was prepared by Takuya Yamanaka and Taghreed Adam. The data and other content provided in the report mobile app were prepared by Katherine Floyd, Irwin Law", "and Hazim Timimi. The app was first developed in collaboration with Adappt in 2019; it has subsequently been maintained by Adappt throughout the year and then updated on an annual basis. The report team is very appreciative of the excellent work done by Adappt. Web-based versions of global, regional and country profiles were prepared by Hazim Timimi. The report team is grateful to various people for their inputs to and advice on report content. Within WHO, particular thanks are due to Bochen Cao, Jessica Ho and Wahyu Retno (Annet) Mahanani for their review of content related to estimates of TB disease burden; and to Gabriela Flores Pentzke Saint-Germain and Hapsatou Toure for their review of material related to TB financing and UHC. Outside WHO, the team is grateful to Zaid Tan- vir (TB Alliance, United States of America) and Jennifer Woolley (International AIDS Vaccine Initiative, United States of America) for their contributions to report con - tent related to TB research. Funding for the production of the report was pro - vided by the governments of China and France. WHO acknowledges with gratitude their support. In addition to the core report team and those men - tioned above, the report benefited from inputs from many staff working in WHO regional and country offices and hundreds of people working for national TB pro - grammes or within national surveillance systems who contributed to the reporting of data and to the review of report material prior to publication. These people are listed below, organized by WHO region. Among the WHO staff listed below, the report team is particularly grateful to Jean Louis Abena Foe, Pedro Avedillo, Vineet Bhatia, Martin van den Boom, Michel Gasana, Diana Hafez, Akudo Ezinne Ikpeazu, Jean de Dieu Iragena, Santosha Kelamane, Giorgi Kuchukhidze, Ernesto Montoro, Fukushi Morishita, Kyung Hyun Oh, Md Kamar Rezwan and Askar Yedilbayev for their contri- bution to data collection and validation, and review and clearance of report material by countries in advance of publication.", "ixAcknowledgements WHO staff in regional and country offices WHO African Region Mariama Ba\u00efssa Abdoulaye, Jean Louis Abena, Haruna Adamu, Adjoa Agbodjan-Prince, Precious Andifasi, Nicole Anshambi, Fekadeselassie Mikru Asfaw, Laimi Sofia Nalitye Ashipala, Nay\u00e9 Bah, Tako Ballo, Nurbai Calu, Carolina Car- doso da Silva Gomes, Lastone Chitembo, Sibdou Ghislaine Conombo Kafando, Seydou Ouaritio Coulibaly, Teshome Desta Woldehanna, Ndella Diakhate, Angelie Dzabatou Babeaux, Ana Bella Ekiri Nguie, Ismael Hassen Endris, Omoni- yi Amos Fadare, Fatimetou Zahra Fall, Louisa Ganda, Michel Gasana, Boingotlo Gasennelwe, Jonathan Greene, Sirak Hailu Bantiewalu, Telesphore Houansou, Akudo Ezinne Ikpeazu, Jean de Dieu Iragena, Moses Jeuronlon, Michael Jose, Y\u00e9ba Laconi Kaaga, Mugagga Kaggwa, Nzuzi Katondi, Michael Kayange, Houria Khelifi, Abderahmane Kharchi Tfeil, Aristide D\u00e9sir\u00e9 Komangoya-Nzonzo, Niaboula Kone, Angela Katherine Lao Seoane, Sharmila Lareef-Jah, Winnie Low-Wah, Nomthandazo Lukhele, David Lukudu, Frank Lule, Johnson Lyimo, Tebogo Madidimalo, Paul Mai - nuka, Casimir Manzengo Mingiedi, Micheal Mazzi, Olivia B\u00e9n\u00e9dicte Mbitikon Dotar, Richard Mbumba Ngimbi, Tamba Jacques Millimouno, Nkateko Mkhondo, Lloyd Eric Barro Moussavou, Laurent Moyenga, Christine Musanhu, Aham - ada Nassuri, Fabian Ndenzako, Andr\u00e9 Ndongosi\u00e8me, Moses Mutebi Nganda, Benjamin Musembi Nganda, Mkhokheli Ngwenya, Denise Nkezimana, Ghislaine Nkone Asseko, Spes Caritas Ntabangana, Ajoy Nundoochan, Innocent Bright Nuwagira, Eunice Omesa, Adiele Nkasiobi Onyeze, Mohamed Ould Sidi Mohamed, Mahamat Djarma Oumaima, Jagne Oumie, Henintsoa Rabarijaona, Muhayimpundu Ribakare, Yatta Sackie Wapoe, Saliyou Sanni, Kafui Senya, Dani\u00e8le Simnoue, Jessica Veiga Soares, Fatim Tall, Evelyne Tibananuka , Siaka Toure, Daisy Trovoada, Assefash Zehaie. WHO Region of the Americas Zohra Abaakouk, Monica Alonso, Angel Alvarez, Kleydson Alves, Fiona Elizabeth Anthony, Miguel Angel Arag\u00f3n, Eden Augustus, Pedro Avedillo, Susana Borroto, Ana Botello, Olivia Brathwaite, Rainier Escalada, Emmanuel Forlack, Gerson Galdos C\u00e1rdenas, Ana de la Garza, Guillermo Gonzalvez, Monica Guardo, Lourdes Guti\u00e9rrez Romero, Frank - lin Hernandez, Reynold Hewitt, Wendy Idiaquez, Sandra Jones, Serene Joseph, Oscar Martin Mesones Lapouble, Raquel Mahoque, Belkys Marcelino, Ernesto Montoro, Romeo Montoya, Stephen Nurse Findlay, Gabriela Rey, Eliz - abeth Rodriguez, Grisel Rodriguez, Hans Salas, Maria Jesus Sanchez, Prabhjot Singh, Nicole Helene Slack-Liburd, Katrina Smith, Aida Soto, Valeska Stempliuk, Daniel Vargas, Jorge Victoria, Marcelo Vila, Neris Villalobos, Gabriela Maria Yerovi, Daniela Zavando. WHO Eastern Mediterranean Region Mohammed Al Abri, Randa Abu Rabe, Mohamed Abukalish, Abdoulkader Ali Adou, Ziad Aljarad, Adel Al-Jasari, Firas Al Khafagi, Deena Alkhamis, Lora AlSawalha, Ala\u2019a AlShaikh, Moubadda Assi, Awatef Belakhel, Rayana Bou Haka, Zied Bouslama, Batoul Dawi, Nahla Gamal Eldin, Ranan Elnory, Diana Hafez, Alaa Hashish, Hania Husseiny, Narantuya Jadambaa, Asiya Jama,", "Santosha Kelamane, Adnan Khamasi, Laeeq Ahmad Khawaja, Mondher Letaief, Stephanie Moody-Geissler, Ghada Muhjazi, Khaled Nada, Sara Nasr, Ramzi Ouhichi, Alissar Rady, Naimullah Safi, Sindani Sebit, Martin van den Boom, Nevin Wilson, Omid Zamani. WHO European Region Zhanara Bekenova, Stela Bivol, Cassandra Butu, Ana Ciobanu, Andrei Dadu, Georgii Dymov, Soudeh Ehsani, Jamshid Gadoev, Gayane Ghukasyan, Ogtay Gozalov, Sayohat Hasanova, Araksya Hovhannesyan, Giorgi Kuchukhidze, Arta Kuli, Nino Mamulashvili, Artan Mesi, Tufan Nayir, Abdulakhad Safarov, Leyli Shamyradova, Javahir Suleymanova, Alexandru Voloc, Askar Yedilbayev, Saltanat Yegeubayeva, Olha Zaitseva. WHO South-East Asia Region Kenza Bennani, Vineet Bhatia, Rick Brown, Lobzang Dorji, Thiraj Dhakshitha Haputhanthri, Anupama Hazarika, Faiha Ibrahim, Sarah Jamal, Kim Jin Ju, Debashish Kundu, Kallayanee Laempoo, Thet Naing Oo, Sudirikku Hennadige Pad- mal, Shushil Dev Pant, Gautam Rabin, Md Jewel Rana, Md Kamar Rezwan, Nazis Arefin Saki, Badri Thapa, Barsha Thapa, Dongbao Yu. WHO Western Pacific Region Shalala Rafayil Ahmadova, Hemant Bogati, Tsolmon Boldoo, Zhongdan Chen, Maria Regina Christian, Serongkea Deng, Bayo Segun Fatunmbi, Sam Fullman, Deepa Gamage, Philippe Guyant, Clarissa Blanca Halum, Lepaitai Hansell, Tom Hiatt, Setiawan Jati Laksono, Mugagga Malimbo, Fukushi Morishita, Kyung Hyun Oh, Machiko Otani, Amanda Reyes Veliz, Challa Negeri Ruda, Jacques Sebert, Vilath Seevisay, Matthew Shortus, Chun Paul Soo, Somdeth Souk - sanh, Fasihah Taleo, Quang Hieu Vu, Rajendra-Prasad Yadav.", "x Global tuberculosis report 2025 National respondents who contributed to reporting and verification of data WHO African Region Abdelrahim Barka Abderramane, Mmoloki Aboneng, Yaw Adusi-Poku, Dissou Affolabi, Arnaud Baurel Akiera, Sofi - ane Alohalassa, Soumana Alphazazi, Geofrey Amanya, Finarimahefa Tonimihamina Andriamampilantohery, Robert Balama, Mamadou Pathe Balde, Adama Marie Bangoura, Alegre Bembele, Elis\u00e2ngela Bonfim, Ball\u00e9 Boubakar, Arthur Bushman, Herbert Chafulumira, Obioma Chijioke-Akaniro, Ellen Chikoto, Dickens Chimatiro, Rhehab Chimzizi, Adji - ma Combary, Abdoul Karim Coulibaly, Fatou Ti\u00e9p\u00e9 Coulibaly, In\u00e1cio Alfredo da Costa, Semoa da Trindade, Ramatou Dagnogo Soumahoro, Fod\u00e9 Danfakha, Muhammed Lamin Darboe, Dami\u00e3o Das Dores Victoriano Ant\u00f3nio, Sessi Dedehouanou, John Deng, Abraham Dhel, Adama Diallo, Mamadou Diongue, Mamadou Diop, Ambr\u00f3sio Disadidi, Sicelo Dlamini, Alzira do Rosario, Marta Isabel dos Santos Freire Monteiro, Bossou Blaise Ekanza, Antoine Depadou Etoundi Evouna, Juan Eyene Acuresila, Yakhokh Fall, Herv\u00e9 Gildas Gando, Evariste Gasana, Abdou Gafarou Gbad - amassi, Belaineh Girma, Marie Gomez, Sestabile Gulwako, Santiago Izco Esteban, Seedy Jaiteh, Taye Letta Janfa, Benedita Jos\u00e9, Vincent Kamara, Elhadj Malick Kane, Clara Chola Kasapo, Immaculate Kathure, Fungai Kavenga, Colette Kinkela, Riziki Kisonga, Sidney Kololo, Madina Konate, David Korboi, Josephine Amie Koroma, Kouakou Jac- quemin Kouakou, Rajiv Kumar, Felix Kwami Afutu, Gertrude Lay Ofali, Isack Lekule, Phany Fleur Lignegnuet, Henry Luzze, Llang Bridget Mabatloung Maama Maime, Daniel Mabirizi, Raimundo Machava, Mariama Mahmoud, Chaibou B\u00e9gou Maimouna, Mpho Maketekete Khesa, Jean Pierre Malemba, Bheki Mamba, Str\u00e9dice Manguinga Guitouka, Saandi Maoulida, Romantiezer Robert Mbassa, Kuzani Mbendera, Marie-L\u00e9opoldine Mbulula Mawagali, Amanuel Hadgu Mebrahtu, Patrick Migambi, Tuduetso Molefi, Louine Morel, Christine Mosi, Angel Mubanga, Robson Mukwiza, Lindiwe Mvusi, Innocent Mwaluka, Stella Mwanjute, Victor Mwemezi, Anne Mwenye, Aboubacar Mzembaba, Judith Mzyece, Manners Ncube, Euphrasie Ndihokubwayo, Norbert Ndjeka, Kwenziweyinkosi Ndlovu, Siphiwe Ngwenya, Winnie Estelle Marie Nkana Yiki, Appolonie Tecla Cristelle Noah, Jos\u00e9lyne Nsanzerugeze, Trust Nyondo, Louis Nzitun- ga, M\u00e9diatrice Nzotuma, Franck-Hardain Okemba-Okombi, Olawumi Olarewaju, Abdelhadi Oumar, Joseph Panyuan, Liliana Pereira, Thato Joyce Raleting Letsie, Emile Ramaroson, Ramprakash Reesaul, Adulai Gomes Rodrigues, Aiban Ronoh, Patrick Rukundo, Nunurai Ruswa, Kantara Sacko, Agbenyegan Samey, Neni Samuel, Tandaogo Saouadogo, Rufus Saye, Cebsile Shabangu, Labaran Shehu, Hilarius Shilomboleni, Paul Shimba, Djenebou Sidibe Djire, Tienabe Siene, Bakary Sirageou, Nicholas Siziba, Michel Harison Tiaray, Abdallahi Traor\u00e9, Titi Tsholofelo, Phillip Tumwesigye, Adrien Ware, Mardemn Yeasuen, Ali Mohamed Zakir, Amtatachew Moges Zegeye, Shaun Zisengwe. WHO Region of the Americas Leandra Abarca, Sarita Aguirre, Edwin Aizpur\u00faa, Antonieta Alarcon Guizado, Xochil Alem\u00e1n de Cruz, Gabriela Amaya Lopez, Aisha Andrewin, Tiemi Arakawa, Fabiola Arias, Sandra Ariza", "Matiz, Carla Ayala, Carlos Alberto Marcos Aya - la Luna, Engels Ilich Banegas Medina, Adriana Chacon, Shawn Charles, Maia Chernomoretz, Karolyn Chong, Jesse Chun, Eric Commiesie, Mariela Contrera, Clara de la Cruz, DyJuan DeRoza, Fernanda Dockhorn Costa Johansen, Ana- sia Edwards, Nadia Escobar Salinas, Mercedes Espa\u00f1a, Hugo Fernandez, Andres Fern\u00e1ndez, Cecilia Figueroa Benites, Greta Franco, Gail Gajadhar, Alrisa Gardiner, Harry Geffrard, Quacy Grant, Claudia Gutierrez, Mary Hatton de Heeck - eren, Maria Henry, Iralice Jansen, Sarah Jbara, Glenise Johnson, Diana Lawrence, Maria de los Angeles Le\u00f3n, Claudia Llerena Polo, F\u00e1tima Leticia Luna L\u00f3pez, Marina Macedo, Eug\u00e8ne Maduro, Andrea Yvette Maldonado Saavedra, Rosa Gabriela Mamani Ala, Daniele Maria Pelissari, Alina Martinez, Maria Rosarys Martinez, Miguel Angel Martinez, Arman - do Mart\u00ednez Guarneros, Mar\u00eda de Lourdes Mart\u00ednez Olivares, Harmonie Massiah, Meryl McQueen, Ang\u00e9lica Medina, Nicole Menezes de Souza, Alexandra Montoya Espinosa, Francis Morey, Franchina Murillo, Carla Newton, Ismenia Raquel Pav\u00f3n Valeriano, Julio P\u00e9rez, Carla Belen Pinilla, Tomasa Portillo Esquivel, Shaun Ramroop, Milo Richard, Tyrone Roberts, Myrian Rom\u00e1n, Samanta Rosas, Arelisabel Ru\u00edz, Sateesh Sakhamuri, Ruth del Carmen Salas Urdane- ta, Wilmer Salazar, Maritza Samayoa Pelaez, Tania Samudio, Ingrid S\u00e1nchez, Karla Mar\u00eda S\u00e1nchez Mendoza, Natasha Serrette, Santhusia Sewdien, Ahmed Shalauddin, Hibeb Alejandra Silvestre Tuch, Nicola Skyers, Natalia Sosa, Mario Rafael Soto Villalta, Michelle Trotman, Melissa Valdez, Daniel V\u00e1zquez, Yohann White, Haneef Wilson, Jennifer Wil - son, Alesia Worgs, Oritta Zachariah, Cesar Mauricio Zelaya. WHO Eastern Mediterranean Region Idil Abdirahim, Suhaib Abu Failat, Ihssane Aharrri, Bilal Ahmad, Shahnaz Ahmadi, Asad Ahmed, Abdullatif Al Khal, Nadia Al-Ani, Mahmoud Al-Baour, Kaltom Alhami, Abdulbari Al-Hammadi, Omar Al-Jaff, Nada Almarzoqi, Ehab Al-Sakkaf, Layth Al-Salihi, Haya Alsanan, Mohamed Alsarraj, Haleema Alserehi, Awatef Alshammeri, Kifah Alshaqeldi, Razan Al-Tarabishi, Khalsa Al-Thuhli, Fatma Al-Yaquobi, Wagdy Amin, Ali Mohammad Amin, Imane Chelloufi, Joanne Daghfal, Driss Daoudi, Mohammad Zaher Dildar, Malika El Ouahabi, Mohamed Furjani, Sara Gempi, Rasheeda Hamid, Diaa Hjaija, Ahmad Ismail, Ibrahim Maia, Ahmed Mankhi, Badeeha Mansoor, Mohamed Mohamed, Afaf Mohamed,", "xiAcknowledgements Mahshid Nasehi, Yassir Piro, Najia Rasheed, Salma Saad, Radia Sabouni, Muhammad Zia Samad, Mohammed Sghiar, Saeed Sharafi, Faisal Siraj, Sabira Tahseen, Hiam Yaacoub, Abdikadar Youssouf Aden, Moinullah Zafari. WHO European Region Ruslan Abdullaev, Malik Adenov, Irada Akhundova, Salikhzhan Alimov, Thomas Althaus, Ekkehardt Altpeter, Elena Arbuzova, Trude Margrete Arnesen, Antoinette Attard, Ewa Augustynowicz-Kope\u0107, Zaza Avaliani, Agnes Bakos, Fun - da Baykal, Snjezana Brckalo, Isabel Carvalho, Mamuka Chincharauli, Nicoleta Valentina Cioran, Andrei Corloteanu, Sharon Cox, Valeriu Crudu, Manfred Danilovits, Edita Davidavi\u010dien\u0117, Teresa Domaschewska, Rovshan Dzhumayev, Albana Fico, Margaret Fitzgibbon, Mireia Garcia Carrasco, Federico Giannoni, Marta Gomes, Biljana Grbav\u010devi\u0107, Irina Gubankova, Jean-Paul Guthmann, Maria Helmrich, Zaida Herrador, Ur\u0161ka Hribar, Afaq H\u00fcseynova, Edgebay Ishanova, Sarah Jackson, Gulnora Jalilova, Jerker Jonsson, Eduard Kabasakalyan, Olim Kabirov, Abdullah Kadyrov, Gulmira Kalmambetova, Guljamol Kasymova, Anush Khachatryan, Sigrid Kiermayr, \u0160pela Klemen, Dmitry Klimuk, Blerina Kodra, Fiona Koeltringer, Maria Korzeniewska-Kosela, Stefan Kroeger, Elena Krotkova, Nino Lomtadze, Zvjezdana Lovri\u0107 Makari\u0107, Stevan Lu\u010di\u0107, Philipp Ludin, Inna Mammadova, Francesco Maraglino, Tanya Melillo, Don - ika Mema, Sheker Mommyeva, Birut\u0117 Nak\u010derien\u0117, Edibe Nurzen Naml\u0131 Bozkurt, Zorica Nanovic, Alena Nikolenka, Karine Nordstrand, Adam Nowi\u0144ski, Cholpon Nurgazieva, Mihaela Obrovac, Mary O\u2019Meara, Kremena Parmakova, Nargiza Parpieva, Sivan Haia Perl, Goranka Petrovi\u0107, Koryun Poghosyan, Georgeta Gilda Popescu, Liudmyla Prylepi - na, Michelle Raess, Ieva Rim\u0161\u0101ne, Jerome Robert, Elisabeth Sandt, Monica Sane Schepisi, G\u00e9rard Scheiden, Christine Schwarz, Anita Segli\u0146a, Armine Serobyan, Firuza Sharipova, Vinciane Sizaire, Nils Skovgaard, Erika Slump, Hanna Soini, Ivan Solovic, Sergey Sterlikov, Maja Stosic, Jana Svecova, Petra Svetina, Silva Tafaj, Sevinc Tagiyeva, Ilia Tasev, Geraldine ter Linde, Yana Terleeva, Mariona Tuneu Valls, United Kingdom Health Security Agency TB Unit Surveil - lance team, Shahnoza Usmonova, Ziyovuddin Valiev, Laima Vasiliauskaite, Irina Vasilyeva, Anne Vergison, Piret Viiklepp, Valentina Vilc, Phong Vu, Tali Wagner, Ji\u0159\u00ed Wallenfels, Angelina Yaneva, Dmitry Zhurkin, Iva Zraki\u0107. WHO South-East Asia Region Shanta Achanta, Bhogendra Acharya, Sanjida Anjum, Md Ataur Rahman Bhuiya, Paranjoy Bordoloi, Mizaya Cader, Shivani Chandra, Ashish Chaudhary, Sandeep Chauhan, Dhrubajyoti Deka, Mrigen Deka, Rinchen Dema, Tsheltrim Dema, Veena Dhawan, Vinay Garg, Divya Gupta, FM Monirul Haque, Hawwa Shamaa Hassan Rasheed, Atkia Faiza Hoque, Lok Raj Joshi, Shiv Joshi, Md Zahangir Kabir, Il Nam Kang, Jyoti Kayesth, Ahmadul Hasan Khan, Sophia Khu - mukcham, Rahul Kumar, Nishant Kumar, Bhawani Singh Kushwaha, Sonam Tshoki Lhamu, Constantino Lopes, Sanjay Mattoo, Zubaida Nasreen, Tun Oo, Gracinda Orleans Tilman, Onali Rajapakshe, Raghuram Rao, Pirabu Ravanan, Abu Sayem Muhammad Shafin, Pramitha Shanthilatha, Urvashi Singh, Antonio Soares, Vigneshwaran", "Somasundaram, Wilawan Somsong, Radha Taralekar, Phurpa Tenzin, Janaka Thilakarathne, Shree Ram Tiwari, Kraisorn Tohtubtiang, Karchung Tshering, Shakila Yeasmin. WHO Western Pacific Region Siti Hafsah Abdul Halim, Asad Abdullahi, Shazelin Alipitchay, Renata Amos, Marvin Apas, Adilah Aziz, Nurul Badriyah, Ladong Belari, Luse Buinimasi, Risa Bukbuk, Kwok Chiu Chang, Wei Chen, Cl\u00e9ment Couteaux, Alice Cuenca, Luis Desquitado, Maremie Diaz, Luong Dinh Van, Maria Alezandra Eguia, Mayleen Jack Ekiek, Meilina Farikha, Clement Filisetti, Angela Patolo Fineanganofo, Ludovic Floury, Gantungalag Ganbaatar, Dorj Gantsetseg, Lizzie Gorrell, Nor Azian binti Haji Hafneh, Chan Yuda Huot, Donekham Inthavong, Vongkham Inthavong, Audrey Jack, Henry Kako, Xaysomvang Keodavong, Martina Kifrawi, Jinsun Kim, Jieun Kim, Phonesavanh Kommanivanh, Oscilyna Kulatea, Win Mar Kyaw, Thi Hai Minh Le, Seung Eun Lee, Shuk Nor Maria Lee, Hyewon Lee, Liza Lopez, Brassicae Mabansag, Charisse Malbacias, Kevin Carter Marafi, Benhur Matalavea, Jane Matanaicak, Chima Mbakwem, Krisia Denise Misa, Serafi Moa, Suzana Mohd Hashim, Enkhnaran Myagmar, Deborah Hee Ling Ng, Binh Hoa Nguyen, Herolyn Nindil, Chanly Nou, National Tuberculosis Advisory Committee (Australia), Akihiro Ohkado, Connie Olikong, Tiffany Tiara Pakasi, Ilagina Pepeuga, Teau Puna, Bereka Reiher, Evonne Sablan, Vaimaila Salele, Eunjung Shin, Anousone Sisou - vanh, Sulistyo Sulistyo, Senolyn Syne, Lai Bun Tai, Joseph Takai, Lia Tanabose, Annie Teannaki, Sivanna Tieng, Marou Tikataake, Vivian Toaniso, Ka In U, Kazuhiro Uchimura, Wareti Uriam, Du Xin, Yan Lin Zhao.", "xiii Abbreviations AIDS acquired immune deficiency syndrome ART antiretroviral therapy BCG bacille Calmette-Gu\u00e9rin BRICS Brazil, the Russian Federation, India, China and South Africa CSV comma separated value CI confidence interval COVID-19 coronavirus disease 2019 ECDC European Centre for Disease Prevention and Control GDP gross domestic product GHO Global health observatory HBC high burden country HIV human immunodeficiency virus IGRA interferon-gamma release assay IHME Institute for Health Metrics and Evaluation ILO International Labour Organization LF-LAM lateral flow urine lipoarabinomannan assay LMICs low- and middle-income countries MAF-TB multisectoral accountability framework for TB MDR-TB multidrug-resistant TB NTP national TB programme OECD Organisation for Economic Co-operation and Development PPP purchasing power parity PPPR pandemic preparedness, prevention and response RR-TB rifampicin-resistant TB SCI service coverage index SDG Sustainable Development Goal SHA System of Health Accounts TB tuberculosis TPT tuberculosis preventive treatment UHC universal health coverage UI uncertainty interval UN United Nations UNAIDS Joint United Nations Programme on HIV/AIDS UNPD UN Population Division USAID United States Agency for International Development USG government of the United States of America VR vital registration WHO World Health Organization WRD WHO recommended rapid diagnostic test XDR-TB extensively drug-resistant TB", "12% reduction 29% reduction 100% 0% 47% 54% 78% 44% 25% US$ 5.9 billion Global TB milestones and targets: latest statusa of progress TPT, TB preventive treatment. a This is the end of 2024 for all indicators unless otherwise stated. b This indicator is not the same as the SDG indicator for catastrophic health expenditures. See Box 3 for further explanation. c The value is the percentage of the general population covered by at least one social protection benefit, with the value for each country weighted according to its share of global TB case notifications. The unweighted value is 52%. d The length of the arrow represents 2 years (out of five) since the 2023 UN-high level meeting onTB. End TB Strategy, 2025 milestones TB incidence rate Percentage of TB-affected house- holds facing catastrophic costs b 50% reduction by 2025, compared with 2015 75% reduction by 2025, compared with 2015 Zero by 2025 2023 UN high-level meeting on TB, targets People diagnosed with TB who were initially tested with a WHO-recommended rapid test Funding: universal access to TB prevention, diagnosis, treatment and care Funding: TB research New TB vaccines that are safe and effective d 6 in Phase III trials, as of August 2025 Rollout initiated, preferably within 5 years Number of TB deaths 100% by 2027 90% by 2027 100% by 2027 90% by 2027 US$ 22 billion annually by 2027 US$ 1.2 billion in 2023 US$ 5 billion annually by 2027 Coverage ofTB diagnosis and treatment Coverage of health & social benefits c TPT coverage: household contacts 58%TPT coverage: people living with HIV 90% by 2027", "1 1. Introduction Tuberculosis (TB) is a preventable and usually curable disease. Nonetheless, more than 10 million people continue to fall ill with TB every year and more than 1 million die from the disease, making it the world\u2019s leading cause of death from a single infectious agent and among the top 10 causes of death worldwide. Urgent action is required to end the global TB epidem - ic by 2030, a goal that has been adopted by all Member States of the United Nations (UN) and the World Health Organization (WHO) (1, 2). TB is caused by the bacillus Mycobacterium tubercu- losis, which is spread when people who are sick with TB expel bacteria into the air (e.g. by coughing). About a quarter of the global population is estimated to have been infected with TB (3). Following infection, the risk of developing TB disease is highest in the first 2 years (approximately 5%), after which it is much lower (4).1 Some people will clear the infection (5, 6). Of the total number of people who develop TB disease each year, about 90% are adults, with more cases among men than women. The disease typically affects the lungs (pulmo - nary TB) but can affect other sites as well. Basic facts about TB are provided in Annex 1 . Without treatment, the death rate from TB disease is high (close to 50%) (7). With the treatments current - ly recommended by WHO (a course of anti-TB drugs for 4\u20136 months), about 90% of people with TB can be cured. Regimens of 1\u20136 months are available to treat TB infection. Universal health coverage (UHC), which means that everyone can obtain the health services they need without suffering financial hardship, is nec - essary to ensure that all people who need treatment for TB disease or infection can access it. The number of people acquiring infection and developing disease (and, in turn, the number of deaths caused by TB) can also be reduced through multisectoral action to address broad- er determinants of TB, such as poverty, undernutrition, HIV infection, smoking and diabetes. Some countries have already reduced their bur - den of TB disease to fewer than 10 cases and less than one death per 100 000 population per year. Research breakthroughs (e.g. a new vaccine) are needed to rap - idly reduce the global number of cases and deaths each year", "to the levels already achieved in these low-burden countries. 1 For people with a long-established infection, empirical data suggest an annual risk of about 10\u201320 per 100 000 individuals. Political commitment to ending the TB epidemic has stepped up in recent years. The UN has held two high-level meetings on TB: the first in 2018 (8) and the second in 2023. The political declaration at the 2023 meeting reaffirmed existing commitments and targets set in the UN Sustainable Development Goals (SDGs) and the WHO End TB Strategy, and included new ones for the period 2023\u20132030 (9). A third UN high-level meet- ing on TB is scheduled for 2028. WHO has published a global TB report every year since 1997. Its main purpose is to provide a compre - hensive and up-to-date assessment of the status of the TB epidemic and progress in the response at global, regional and national levels, in the context of global TB commitments, strategies and targets. As with previous global TB reports, this 2025 edi - tion is based primarily on data gathered by WHO from national ministries of health in annual rounds of data collection. In 2025, 184 countries and areas (out of 215) with more than 99% of the world\u2019s population and TB cases reported data (Annex 2 ), including all high TB bur- den countries ( Annex 3 ). Data from the WHO mortality database and Global Health Observatory (GHO) as well as databases maintained by other UN agencies and the World Bank are also used. The report has three components: a short \u201ccore\u201d report that focuses on the main findings and messages (this document); webpages that provide more detailed and digitized information, including a large number (>100) of interactive graphics; 2 and an app that con - tains country, regional and global profiles. This format ensures that all content is readily available in relatively small and \u201cbite-sized\u201d chunks, facilitating access, navi - gation, reading and use. All data and estimates can be downloaded from WHO\u2019s online global TB database (10). The top findings and messages of the 2025 report are highlighted in Box 1 . 2 There are 16 webpages organized according to six \u201cstandard\u201d topics: TB disease burden; TB diagnosis and treatment; TB prevention and screening; TB financing; UHC and TB determinants; and TB research. There are also webpages on four \u201cfeatured topics\u201d. These are the third (2023) national TB prevalence", "2 Global tuberculosis report 2025 Box 1. Top findings and messages in the 2025 report TB remains a major global public health problem and progress in reducing the burden of disease falls far short of 2030 targets in most parts of the world. Nonetheless, after setbacks during the COVID-19 pandemic, most indicators are moving in the right direction and there are regional and country success stories. Changes in the funding landscape threaten this progress. Globally in 2024, an estimated 10.7 million people (95% uncertainty interval [UI]: 9.9\u201311.5 million) fell ill with TB (incident cases) and 1.23 million died from the disease (95% UI: 1.13\u20131.33 million). a The TB incidence rate (new cases per 100 000 population per year) was 131 (95% UI: 122\u2013141) and the case fatality rate was 11.5%. TB is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. Most of the people who develop TB disease each year are in 30 high TB burden countries: they accounted for 87% of the global total in 2024. The top eight (67% of the worldwide total) were India (25%), Indonesia (10%), the Philippines (6.8%), China (6.5%), Pakistan (6.3%), Nigeria (4.8%), the Democratic Republic of the Congo (3.9%) and Bangladesh (3.6%). In 2024, 54% of people who developed TB were men, 35% were women and 11% were children. Globally, the absolute number of people falling ill with TB decreased in 2024 for the first time since 2020, following 3 consecutive years of increases (2021\u20132023) due to COVID-related disruptions to TB diagnosis and treatment. The total of 10.7 million was a small (1%) reduction from 10.8 million in 2023, but still above the level of 2020 (10.3 million). There was a larger (1.7%) global decline in the TB incidence rate between 2023 and 2024; at 131 per 100 000 population in 2024, this was back to the level of 2020. The net reduction from 2015 to 2024 was 12%, far from the End TB Strategy milestone of a 50% reduction by 2025 and the target of an 80% reduction by 2030. Globally, the number of deaths caused by TB also fell in 2024. The total of 1.23 million was a 3% reduction compared with 1.27 million in 2023. The net reduction from 2015 to 2024 is more impressive, at 29%, but still far from the End TB Strategy milestone of a", "75% reduction by 2025 and the target of a 90% reduction by 2030. Much better progress in reducing the burden of TB disease has been made in some regions and countries. Between 2015 and 2024, the WHO African Region achieved a 28% reduction in the TB incidence rate and a 46% reduction in the number of TB deaths. The WHO European Region achieved reductions of 39% and 49%, respectively. 101 countries achieved reductions of at least 20% in the TB incidence rate and 65 achieved reductions of at least 35% in the number of TB deaths. b Further reductions in the burden of TB disease require improvements in the coverage of TB diagnostic, treatment and preventive interventions; action on broader determinants that drive new infections or increase the risk of developing disease once infected; and technological breakthroughs, such as a new TB vaccine. All depend on adequate funding. Globally, 8.3 million people were reported as newly diagnosed with TB in 2024 \u2013 a small increase from 8.2 million in 2023 and 78% (95% UI: 72\u201384%) of the estimated number of incident cases. Of these, 54% were initially tested with a rapid test, up from 48% in 2023. A total of 164 545 people were treated for rifampicin- resistantc TB (RR-TB) in 2024. This was 42% of the approximately 390 000 people who developed RR-TB in 2024, almost the same as in 2023. The treatment success rate for drug-susceptible TB remains high, at 88%, and has improved to 71% for RR-TB. From 2000\u20132024, treatment of people with TB is estimated to have averted 83 million deaths. Globally, 5.3 million people at high risk of developing TB disease were provided with TB preventive treatment (TPT) in 2024: 3.5 million close contacts of people diagnosed with TB and 1.8 million people living with HIV. TPT coverage was 58% among people living with HIV (up from 56% in 2023) and 25% among household contacts (up from 20% in 2023). One of the barriers to accessing TB diagnosis and treatment is the costs faced by people with TB and their households; about 50% face costs that exceed 20% of annual household income. Reducing this economic burden requires faster progress towards UHC and better levels of social protection. In most high TB burden countries, less than 50% of the general population has access to at least one social protection benefit and values for the UHC service", "coverage index (SCI) are in the range 40\u201360 (out of 100). Key drivers of the TB incidence rate at country level include income per capita and the prevalence of undernutrition, HIV infection, diabetes, smoking and alcohol use disorders. There are 18 TB vaccines in clinical development, including six in Phase 3 trials. Funding for the TB response remains grossly inadequate and has been stagnating. Funding for provision of TB prevention, diagnosis and treatment amounted to US$ 5.9 billion in 2024, and funding for TB research was US$ 1.2 billion in 2023. d These figures are 27% and 24%, respectively, of the global targets of US$ 22 billion and US$ 5 billion annually by 2027. Cuts to international donor funding from 2025 onwards threaten overall funding for the TB response in many countries. Achieving the goal of ending the global TB epidemic, to which all WHO and UN Member States have committed, requires further intensification of efforts. Following cuts in international donor funding in 2025, political commitment and domestic funding in high TB burden countries are more important than ever. a This included 1.08 million among HIV-negative people and 150 000 among people with HIV (officially classified as deaths from HIV/AIDS). b These reductions correspond to the 2020 milestones of the End TB Strategy ( Box 2 ). c Rifampicin is the most powerful first-line anti-TB drug. d The source of this figure is the latest report on funding for TB research published by Treatment Action Group.", "3 2. Global TB commitments, strategy and targets In 2014 and 2015, all WHO and UN Member States committed to ending the TB epidemic, through their adoption of WHO\u2019s End TB Strategy ( Box 2 ) and the UN SDGs (1, 2, 11) . The strategy included milestones (for 2020 and 2025) and targets (for 2030 and 2035) for large reductions in the TB incidence rate (new cases per 100 000 population per year), the absolute number of deaths caused by TB, and costs faced by people with TB and their households. Key requirements to reach the milestones and targets were defined within the three pillars of the End TB Strat- egy ( Box 2 ). They included provision of TB prevention, diagnostic and treatment services within the context of progress towards UHC and social protection; multi - sectoral action to address broader social and economic determinants of TB that drive new infections or increase the risk of developing disease once infected; and tech - nological breakthroughs, such as a new TB vaccine. The third target of the End TB Strategy is that no TB-affected households face costs that are catastroph - ic.1 This target was set in recognition of the fact that removal of financial and economic barriers to accessing TB diagnosis and treatment is a prerequisite for achiev - ing the milestones and targets for reductions in TB 1 This indicator is not the same as the SDG indicator for catastrophic health expenditures (see Box 3 ). incidence and TB mortality. \u201cCatastrophic\u201d is defined as total costs (direct medical expenditures, direct non - medical expenditures and indirect costs such as income losses) that exceed 20% of annual household income. Further details about the rationale for the milestones and targets and how they were defined are available elsewhere (12). Within the SDG monitoring framework (2016\u20132030), the indicator being used to monitor progress towards ending the TB epidemic is the TB incidence rate. A global ministerial conference on TB was held in 2017, the outcome of which was the Moscow Declaration (13). This was followed less than a year later by the first-ever UN high-level meeting on TB, at which commitments to the SDGs and End TB Strategy were reaffirmed and new ones added (8). Global targets for mobilization of fund - ing and provision of treatment were established for the first time, covering the period 2018\u20132022. Assessment of the", "extent to which these targets were achieved was part of WHO\u2019s Global tuberculosis report 2023 (14). A second UN high-level meeting was held in 2023. The political declaration (9) included new commitments and targets for the period 2023\u20132030 ( Table 1 , Table 2 ). The targets are for the coverage of rapid diagnostic testing, TABLE 1 Global targets set in 2023 at the second UN high-level meeting on TB INDICATOR GLOBAL TARGET Coverage of rapid diagnostic testing for TB (the annual number of people diagnosed with TB who were initially tested using a WHO-recommended rapid diagnostic test, as a percentage of the number of people diagnosed with TB in the same year) 100% by 2027 Coverage of TB diagnosis and treatment (the annual number of people provided with quality-assured TB diagnosis and treatment, as a percentage of the estimated number of people who developed TB disease in the same year) 90% by 2027 (equivalent to up to 45 million people globally in the 5-year period 2023\u20132027) Coverage of health and social benefits package for people with TB 100% by 2027 Coverage of TPT (the annual number of people at high risk of developing TB disease who were provided with TPT, as a percentage of the estimated number of people eligible for treatment in the same year) 90% by 2027 (equivalent to up to 45 million people globally in the 5-year period 2023\u20132027: up to 30 million household contacts of people with TB and up to 15 million people living with HIV) Annual funding for universal access to quality prevention, diagnosis, treatment and care for TB US$ 22 billion by 2027, US$ 35 billion by 2030 Annual funding for TB research US$ 5 billion by 2027 Availability of new TB vaccines that are safe and effective Rollout initiated, preferably within 5 years", "4 Global tuberculosis report 2025 Box 2. The End TB Strategy at a glance VISION A WORLD FREE OF TB \u2014 zero deaths, disease and suffering due to TB GOAL END THE GLOBAL TB EPIDEMIC INDICATORS MILESTONES TARGETS 2020 2025 2030 2035 Percentage reduction in the absolute number of TB deaths a (compared with 2015 baseline) 35% 75% 90% 95% Percentage reduction in the TB incidence rate (compared with 2015 baseline) 20% 50% 80% 90% Percentage of TB-affected households facing catastrophic total costs due to TB b (level in 2015 unknown) 0% 0% 0% 0% PRINCIPLES 1. Government stewardship and accountability, with monitoring and evaluation 2. Strong coalition with civil society organizations and communities 3. Protection and promotion of human rights, ethics and equity 4. Adaptation of the strategy and targets at country level, with global collaboration PILLARS AND COMPONENTS 1. INTEGRATED, PATIENT-CENTRED CARE AND PREVENTION A. Early diagnosis of TB including universal drug-susceptibility testing, and systematic screening of contacts and high-risk groups B. Treatment of all people with TB including drug-resistant TB, and patient support C. Collaborative TB/HIV activities, and management of comorbidities D. Preventive treatment of persons at high risk, and vaccination against TB 2. BOLD POLICIES AND SUPPORTIVE SYSTEMS E. Political commitment with adequate resources for TB care and prevention F. Engagement of communities, civil society organizations, and public and private care providers G. Universal health coverage policy, and regulatory frameworks for case notification, vital registration, quality and rational use of medicines, and infection control H. Social protection, poverty alleviation and actions on other determinants of TB 3. INTENSIFIED RESEARCH AND INNOVATION I. Discovery, development and rapid uptake of new tools, interventions and strategies J. Research to optimize implementation and impact, and promote innovations a This indicator is for the combined total of TB deaths in HIV-negative and HIV-positive people. Deaths from TB among people with HIV are officially classified as deaths caused by HIV/AIDS, with TB as a contributory cause. b This indicator is not the same as the SDG indicator for catastrophic health expenditures. See Box 3 for further explanation. TB treatment, health and social benefits for people with TB, and TPT; funding for the delivery of TB-related health services and TB research; and the availability of new TB vaccines that are safe and effective. The fund - ing targets were informed by the Stop TB Partnership\u2019s Global Plan to End TB, 2023\u20132030 (15).", "5 TABLE 2 Highlights of commitments and requests at the second UN high-level meeting on TB in 2023 a) Commitments TOPIC OR THEME COMMITMENT Provide comprehensive care to all people with TB Strengthen the provision of comprehensive care for all people with TB, with particular attention to people who are vulnerable or in vulnerable situations (e.g. people with HIV, people with TB-associated disabilities, older people, migrants, refugees, internally displaced people, and pregnant and lactating women), using specific models of care such as nutritional, mental health and psychosocial support, social protection, rehabilitation and palliative care Scale-up comprehensive efforts to close longstanding gaps in the prevention, diagnosis, treatment and care of children Address the crisis of drug- resistant TB Work towards the achievement of universal, equitable and affordable access to WHO-recommended diagnostics and drug susceptibility tests, and all-oral shorter-duration treatment regimens for people with drug-resistant TB, complemented by monitoring and management of side-effects, together with care and support to improve treatment outcomes Build on interlinkages across the global health agendas of TB, UHC and PPPR, to strengthen the TB response Establish TB services as essential elements of national and global strategies to advance UHC, address antimicrobial resistance and strengthen PPPR Integrate systematic screening, prevention, treatment and care of TB, and related health conditions, within primary health care, including community-based health services Invest in public health infrastructure and the health workforce Address TB during health and humanitarian emergencies Safeguard TB services as essential health services during humanitarian and health emergencies Strengthen the engagement of civil society and communities affected by TB Intensify national efforts to create enabling legal and social policy frameworks to combat inequalities, and to eliminate all forms of TB-related stigma, discrimination and other human rights barriers and violations Strengthen the meaningful engagement of parliaments, civil society, and TB-affected local communities, including young people and women, in all aspects of the TB response, to ensure equitable and people- centred access to TB services, with increased and sustained investments, especially in community initiatives Enable and strengthen TB research Create an enabling environment for TB research and innovation across Member States and partners Strengthen research capacity and collaboration through TB research platforms and networks across the public and private sectors, academia and civil society Accelerate the research, development and roll-out of safe, effective, affordable and accessible vaccines, preferably within the next 5 years, including through leveraging global collaboration mechanisms and WHO initiatives such", "as the accelerator council for new TB vaccines Promote access to affordable medicines Promote equitable access to affordable, safe, effective and quality medicines, such as generics, vaccines, diagnostics and health technologies, including through the Stop TB Partnership/Global Drug Facility, to ensure availability and access to quality-assured and affordable commodities recommended by WHO Strengthen multisectoral accountability Support the WHO multisectoral accountability framework for TB by strengthening high-level multisectoral accountability and review mechanisms, in line with national contexts, defining the roles and responsibilities of relevant sectors and stakeholders with the meaningful engagement of people and communities affected by TB Develop and implement ambitious, costed national TB strategic plans or health strategies with a multisectoral approach b) Requests TOPIC OR THEME REQUEST Role of WHO WHO is requested to continue providing global leadership to support Member States to build a resilient response to TB as an integral part of the UHC agenda, and to also address the drivers and determinants of the epidemic, including in the context of health and humanitarian emergencies, with multisectoral engagement, the provision of normative guidance and technical support, and through monitoring, reporting and review of progress, and by advancing the TB research and innovation agenda Report and review progress The UN Secretary-General, with the support of WHO, is requested to report, as part of his annual SDG report, on the global effort to end TB The UN Secretary-General, with the support of WHO, is requested to present a report to the UN General Assembly in 2027, on the progress achieved towards realizing the commitments made in the 2023 political declaration on TB Heads of state and government are requested to undertake a comprehensive review of progress at a UN high-level meeting on TB in 2028 HIV: human immunodeficiency virus; PPPR: pandemic preparedness, prevention and response; SDG: Sustainable Development Goal; UHC: universal health coverage; UN: United Nations; WHO: World Health Organization. 2. Global TB commitments, strategy and targets", "6 Global tuberculosis report 2025 3. Main findings and messages The main findings and messages cover (in order) the fol- lowing topics: \u25b6 estimates of TB disease burden, 1 including the num - ber of people falling ill with TB (incident cases) and drug-resistant TB, the number of deaths caused by TB, progress towards End TB Strategy milestones and targets for reductions in TB incidence and mor - tality, and data required to strengthen estimation of TB disease burden in the years up to 2030; \u25b6 TB diagnosis and treatment, including case notifica - tions of people newly diagnosed with TB, diagnostic testing for TB, knowledge of HIV status among people newly diagnosed with TB, the coverage of TB diagno- sis and treatment, provision of antiretroviral therapy (ART) to people diagnosed with TB who are living with HIV, and treatment success rates; \u25b6 diagnosis and treatment of people with drug-resist - ant TB; \u25b6 TB prevention and screening, with particular atten - tion to TPT; \u25b6 funding for TB services; \u25b6 UHC and results from national surveys of costs faced by TB-affected households; \u25b6 multisectoral action and accountability, with par - ticular attention to social protection, determinants of TB and the WHO multisectoral accountability framework for TB (MAF-TB); and \u25b6 TB research, with particular attention to the latest status of the pipelines for new TB diagnostics, drugs and vaccines. For most of these topics, estimates and data are for the period 2010\u20132024. New content compared with previous editions of the report includes: \u25b6 assessment of the impact of 2025 cuts to internation- al donor funding on TB services using data reported to WHO in 2025, with particular attention to countries that reported receiving grants from the Global Fund and bilateral funding from the United States Agency for International Development (USAID) in 2024; \u25b6 results from the third (2023) national TB prevalence survey in Cambodia, which show impressive reduc - tions in TB disease burden since the first survey in 2002; 1 Updates to methods used to produce estimates of TB disease burden for this report are summarized in Annex 4. \u25b6 assessment of the coverage of social protection using data published by the International Labour Organiza- tion (ILO), with particular attention to high TB burden countries; \u25b6 a listing of countries estimated to have reached the first milestones of the End TB Strategy for reductions in TB incidence and mortality", "between 2020 and 2024; and \u25b6 a categorization of all countries according to their estimated level of TB incidence in 2024, and a corre - sponding list of countries that have changed category (up or down) since 2015 (the baseline year of the End TB Strategy). It is also important to highlight that during the World Health Assembly in May 2025, Indonesia was reassigned to the WHO Western Pacific Region, having previously been part of the South-East Asia Region. 2 In all analyses of trends for WHO regions, Indonesia is included in the WHO Western Pacific Region for the whole of the time series. Number of people developing TB Falling globally, COVID-related increases reversed Globally, the number of people falling ill with TB (inci - dent cases) decreased in 2024 for the first time since 2020, following 3 consecutive years of increases (2021\u2013 2023) due to COVID-related disruptions to TB diagnosis and treatment ( Fig. 1 ).3,4 The total of 10.7 million (95% UI: 9.9\u201311.5 million) in 2024 was a small (1%) reduction from 10.8 million (95% UI: 10.0\u201311.6 million) in 2023. It remained above the level of 10.3 million (95% UI: 9.6\u2013 11.0 million) in 2020. 2 In accordance with resolution WHA78.25 (2025), which was adopted on 27 May 2025. 3 Country or region-specific models have been used to produce estimates of TB incidence and mortality during the period 2020\u20132024, for the subset of countries that experienced considerable disruptions to TB diagnosis and treatment in 2020 or 2021 (defined as TB case notifications that fell by 10% or more in either 2020 or 2021). Reductions in notifications were assumed to reflect reductions in access to diagnosis and treatment (and some level of underreporting), causing an increase in the number of people with undiagnosed TB and in turn both an increase in the number of deaths from TB and increased transmission of infection. With a lag time, increases in transmission result in an increase in the number of people developing TB disease (i.e. TB incidence). Further details are provided elsewhere (14, 16, 17). 4 The major contributors to the global increase between 2020 and 2023 were (in order of the absolute size of their contribution) Indonesia, the Philippines and Myanmar.", "73. Main findings and messages Total People living with HIV Case notifications of people newly diagnosed with TB Total People living with HIV Case notifications of people newly diagnosed with TB 2025 milestone 2010 2015 2020 2024 0 5 10 15 Millions per year 2010 2020 2024 0 50 100 150 200 Rate per 100 000 population per year 2015 FIG. 1 Global trends in the estimated number of incident TB cases (left) and the incidence rate (right), 2010\u20132024 The horizontal dashed line shows the 2025 milestone of the End TB Strategy, which is a 50% reduction in the TB incidence rate between 2015 and 2025. Shaded areas represent 95% uncertainty intervals. There was a larger decline (1.7%) in the global TB inci- dence rate (new cases per 100 000 population per year) 1 between 2023 and 2024 ( Fig. 1 , right panel). At 131 per 1 The report uses the latest population estimates published by the UN Population Division (see Annex 2 ). 100 000 population (95% UI: 122\u2013141) in 2024, this was back to the level of 2020. At regional level, trends in TB incidence rates vary (Fig. 2 ). In 2024, an upward trend in 2020\u20132023 was reversed in the WHO Western Pacific Region. The rate Rate per 100 000 population per year 0 100 200 300 400 0 10 20 30 40 0 100 200 300 400 500 0 20 40 60 0 50 100 150 0 50 100 150 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 African Region Region of the Americas Eastern Mediterranean RegionEuropean Region South-East Asia Region Western Pacific Region FIG. 2 Trends in estimated TB incidence rates by WHO region, 2010\u20132024 The overall TB incidence rate is shown in blue and the incidence rate among people living with HIV is shown in light blue . The black solid lines show case notifications of people newly diagnosed with TB, for comparison with estimates of the overall incidence rate. Shaded areas represent 95% uncertainty intervals. The horizontal dashed line shows the 2025 milestone of the End TB Strategy, which is a 50% reduction in the TB incidence rate between 2015 and 2025. Indonesia is included in the WHO Western Pacific Region for the whole time series.", "8 Global tuberculosis report 2025 FIG. 3 Estimated number of incident TB cases for countries with at least 100 000 incident cases, 2024 a a The labels show the eight countries that accounted for two thirds of the global number of people estimated to have developed TB in 2024. decreased for a second consecutive year in the WHO Eastern Mediterranean and South-East Asia regions, reinforcing the 2023 reversal of a 2020\u20132022 COVID- related upward trend. In the WHO European Region, the TB incidence rate has been falling since 2022. In the WHO African Region, the decline in the TB incidence rate that has been sustained for many years continued in 2024. 1 The most concerning trend was in the WHO Region of 1 In terms of TB case notifications, disruptions to TB diagnosis and treatment during the COVID-19 pandemic were negligible in the WHO African Region. FIG. 4 Global estimates of TB incidence (absolute numbers) disaggregated by age group and sex (female in purple; male in orange), 2024 Dots and error bars show best estimates and 95% uncertainty intervals, respectively. 0\u20134 5\u201314 15\u201324 25\u201334 35\u201344 45\u201354 55\u201364 \u226565 0 0.4 0.8 1.2 Number of cases (millions) Age group (years) the Americas, where the incidence rate increased for the fourth consecutive year, reflecting the estimated impact of shortfalls in TB case detection in 2020 and a still incomplete recovery in 2024. Geographically, most people who developed TB in 2024 were in the WHO regions of South-East Asia (34%), the Western Pacific (27%) and Africa (25%), 2 with small- er proportions in the Eastern Mediterranean (8.6%), the Americas (3.3%) and Europe (1.9%). 3 The 30 high TB burden countries 4 accounted for 87% of all estimated incident cases worldwide, with eight of these countries (Fig. 3 ) accounting for two thirds (67%) of the glob - al total: India (25%), Indonesia (10%), the Philippines (6.8%), China (6.5%), Pakistan (6.3%), Nigeria (4.8%), the Democratic Republic of the Congo (3.9%) and Bangla - desh (3.6%). The top five countries accounted for 55% of the global total. TB can affect anyone, regardless of age or sex (Fig. 4 ). The highest incidence is in adult men (aged \u226515 years 5), with an estimated 5.8 million cases (95% UI: 4.2\u20137.4 mil - lion) in 2024, equivalent to 54% of the estimated total. There were an estimated 3.7 million cases (95% UI: 2.7\u20134.7 million) among adult women", "(aged \u226515 years), equivalent to 35% of the estimated total; and 1.2 mil - 2 Regional shares for the WHO South-East Asia and Western Pacific regions differ from those published in previous reports, following the reassignment of Indonesia to the WHO Western Pacific Region (see above). 3 Regional percentages do not sum to 100 because of rounding. 4 See Annex 3. 5 The age groups for which WHO collects TB case notification data and produces estimates of disease burden are 0\u20134, 5\u201314, 15\u201324, 25\u201334, 35\u201344, 45\u201354, 55\u201364 and \u226565 years. Number of incident cases 100 000 500 000 1 000 000 2 000 000 Nigeria Democratic Republic of the Congo Pakistan India China Bangladesh Philippines Indonesia", "9 3. Main findings and messages lion cases (95% UI: 0.9\u20131.5 million) among children and young adolescents (aged <15 years), equivalent to 11% of the estimated total. The higher share of TB cases among men is consistent with evidence from national TB prevalence surveys, which show that the burden of TB disease is higher among men than women (18). Among all incident cases of TB in 2024, 5.8% were people living with HIV, a decrease from 6.1% in 2023. This proportion has been steadily declining for many years, following a peak at 17% in 2000. The proportion of peo - ple with a new episode of TB (incident cases) who were living with HIV was highest in countries in the WHO Afri - can Region, exceeding 50% in parts of southern Africa. The severity of national TB epidemics \u2013 in terms of the number of incident (new) TB cases per 100 000 popula - tion per year \u2013 varies widely among countries, from less than 10 to more than 500 ( Fig. 5 ). In 2024, 62 countries had a low incidence of TB (<10 new cases per 100 000 population per year). Most of these countries were in the WHO Region of the Americas and the European Region, with the remainder in the Eastern Mediterrane - an and Western Pacific regions. The highest rates were mainly found in countries in the WHO African Region, where 12 countries had a rate of more than 300. Most of the 30 high TB burden countries had a rate of 150\u2012400, but three had a rate of more than 500: Lesotho, Papua New Guinea and the Philippines. In the 10-year period 2015\u20132024, 61 countries moved between the incidence rate categories shown in Fig. 5 ; 52 progressed to a lower category and nine moved to a higher category.1 1 Further details are provided in Annex 3 (see Table A3.3 ). FIG. 5 Estimated TB incidence rates at country level, 2024 Incidence per 100 000 population per year 0\u20139.9 10\u201349 50\u201399 100\u2013299 300\u2013499 \u2265 500 No data Not applicable Number of people developing drug-resistant TB Falling globally since 2015 Drug-resistant TB continues to be a public health threat. Resistance to rifampicin \u2013 the most effective first-line anti-TB drug \u2013 is of greatest concern. TB that is resistant to rifampicin and isoniazid is defined as multidrug-resistant TB (MDR-TB). Both MDR-TB and rifampicin-resistant TB (RR-TB) require", "treatment with second-line drugs. Globally, the estimated annual number of people who developed MDR-TB or RR-TB (MDR/RR-TB) has been falling since 2015 ( Fig. 6 ). The estimated number in 2024 was 390 000 (95% UI: 360 000\u2013430 000). In 2024, FIG. 6 Global trend in the estimated number of people who developed MDR/RR-TB (incident cases), 2015\u20132024 The shaded area represents the 95% uncertainty interval. 0 200 400 600 800 Thousands per year 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024", "10 Global tuberculosis report 2025 FIG. 7 Global trend in the estimated percentage of people with TB who had MDR/RR-TB, 2015\u20132024 The shaded area represents the 95% uncertainty interval. China Philippines FIG. 8 Estimated number of people who developed MDR/RR-TB (incident cases) for countries with at least 1000 incident cases, 2024 a a The labels show the four countries that accounted for more than half of the global number of people estimated to have developed MDR/RR-TB in 2024. Number of cases 1000 10 000 100 000 India Russian Federation the estimated proportion of people with a first episode of TB (new cases) who had MDR/RR-TB was 3.2% (95% UI: 2.5\u20133.9%), a decrease from 4.7% (95% UI: 3.5\u20136.0%) in 2015 ( Fig. 7). The estimated proportion among peo - ple with a previous history of TB treatment was much higher, at 16% (95% UI: 8.3\u201323%) in 2024 ( Fig. 7 ). This was down from 19% (95% UI: 10\u201328%) in 2015. Four countries accounted for more than half of the global number of people estimated to have developed MDR/RR-TB in 2024: India (32%), China (7.1%), the Philip- pines (7.1%) and the Russian Federation (6.7%) (Fig. 8 ). The highest proportions of people with TB who had MDR/RR-TB (>50% of previously treated cases in 2023) were found in Eastern Europe and Central Asia. 1 1 Further details are provided in the report webpages (section 1.3). Deaths caused by TB Continued global fall in 2024 after 2020\u20132021 increases The estimated global number of deaths caused by TB fell for a third consecutive year in 2024, continuing the reversal of increases that occurred during the worst period of COVID-related disruptions to TB diagnosis and treatment in 2020 and 2021 (Fig. 9 ).2 Globally in 2024, TB caused an estimated 1.23 million 2 People with TB who remain undiagnosed and untreated have a higher risk of death than those started on treatment. The impact of disruptions to TB diagnosis and treatment is more immediate for TB mortality and more delayed for TB incidence. Similarly, the impact of recoveries in access to TB diagnosis and treatment is more immediate for TB mortality and more delayed for TB incidence. 0 10 20 30 Percentage 0 2 4 6 Percentage 2015 2016 2017 2018 2019 2020 2021 2022 2023 20242015 2016 2017 2018 2019 2020 2021 2022 2023 2024 People with no previous history of TB treatment People", "113. Main findings and messages deaths (95% UI: 1.13\u20131.33 million), including 1.08 million among HIV-negative people (95% UI: 0.99\u20131.18 million) and 150 000 among people with HIV (95% UI: 120 000\u2013 183 000). 1 This total was down from 1.27 million (95% UI: 1.17\u20131.38 million) in 2023, 1.42 million (95% UI: 1.29\u20131.55 million) in 2019 (pre-pandemic) and a 42% reduction from 2.13 million (95% UI: 1.91\u20132.35 million) in 2010. The case fatality rate was 11.5%.2 Global trends in the number of deaths caused by TB differ by HIV status ( Fig. 9 , Fig. 10 ). Deaths from TB among HIV-negative people have driven the overall trend, with year-on-year reductions up to 2019 followed by increases in 2020 and 2021, 3 and then declines from 2022 to 2024. Deaths from TB among people with HIV have been declining for many years and by 2024 had fallen 76% compared with 2010. The latest year for which WHO has published esti - mates of global deaths by cause is 2021 (Fig. 11 ). In that year, TB was the 10th leading cause of death worldwide and the second leading cause of death from a single infectious agent, after COVID-19. In the WHO African and South-East Asia regions, TB was the fourth and fifth leading cause of death, respectively.4 In 2024, a total of 70 000 deaths from COVID-19 were officially reported to WHO (19). This number does not 1 Deaths from TB among people with HIV are officially classified as deaths from HIV/AIDS. Therefore, a clear distinction between deaths among HIV-negative people and those among people with HIV is made in Fig. 9 , Fig. 10 and Fig. 11 . 2 This is approximated as the number of deaths in 2024 divided by the number of incident cases in 2024. 3 The estimated number of deaths caused by TB among HIV- negative people was 1.18 million (95% UI: 1.06\u20131.30 million) in 2020 and 1.22 million (95% UI: 1.11\u20131.34 million) in 2021. 4 Here, estimates for the WHO South-East Asia Region include Indonesia. FIG. 9 Global trends in the estimated number of deaths caused by TB (left) and the TB mortality rate (right),a 2010\u20132024 The horizontal dashed line shows the 2025 milestone of the End TB Strategy, which is a 75% reduction in the total number of TB deaths between 2015 and 2025. Shaded areas represent 95% uncertainty intervals. a Deaths from TB", "among people with HIV are officially classified as deaths caused by HIV/AIDS in the International Classification of Diseases, with TB as a contributory cause. 2025 milestone People with HIV Total HIV-negative people People with HIV Total HIV-negative people 2010 2015 2020 2024 0 0.5 1 1.5 2 2.5Millions per year 2010 2015 2020 2024 0 10 20 30 Rate per 100 000 population per year account for late reporting or underreporting, 5 but is nevertheless far below the estimated number of deaths from TB. The global number of deaths officially classified as caused by TB in 2024 was almost double the 630 000 (95% UI: 600 000\u2013660 000) caused by HIV/AIDS (20). Regional trends in the number of TB deaths vary (Fig. 12 ). The pattern of reductions up to 2019, fol - lowed by increases during the COVID-19 pandemic and 5 Data for 2024 were reported by 106 countries and areas \u2013 about half the number that reported in previous years. FIG. 10 Global trends in the estimated number of deaths caused by TB and HIV (in millions), 2010\u20132024 a,b Shaded areas represent 95% uncertainty intervals. a For HIV/AIDS, the latest estimates of the number of deaths in 2024 that have been published by UNAIDS are available at http://www.unaids.org/en/ (accessed 31 July 2025). For TB, the estimates for 2024 are those published in this report. b Deaths from TB among people with HIV are officially classified as deaths caused by HIV/AIDS in the International Classification of Diseases, with TB as a contributory cause. HIV deaths TB deaths in HIV-negative people TB deaths in people with HIV 2010 2012 2014 2016 2018 2020 2022 2024 0 0.5 1.0 1.5Millions per year", "12 Global tuberculosis report 2025 FIG. 11 Top 15 causes of death worldwide in 2021 a,b Deaths from TB among people with HIV are shown in grey. a This is the latest year for which estimates for all causes are currently available. See WHO estimates, available at https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death . b Deaths from TB among people with HIV are officially classified as deaths caused by HIV/AIDS in the International Classification of Diseases, with TB as a contributory cause. 0 123 45 678 91 0 Number of deaths (millions) Colon and rectum cancers Road injury Diarrhoeal diseases Cirrhosis of the liver Hypertensive heart disease Tuberculosis Kidney diseases Diabetes mellitus Alzheimer disease and other dementias Trachea, bronchus, lung cancers Lower respiratory infections Chronic obstructive pulmonary disease Stroke COVID-19 Ischaemic heart disease African Region 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 10 20 30 40 50 60 30 50 70 90 110 50 100 150 200 250 300 350 300 500 700 900 1100 10 20 30 200 400 600 800 1000 Thousands per year Region of the Americas Eastern Mediterranean RegionEuropean Region South-East Asia Region Western Pacific Region FIG. 12 Trends in the estimated absolute number of TB deaths (HIV-negative people and people with HIVa) by WHO region, 2010\u20132024 Shaded areas represent 95% uncertainty intervals. The horizontal dashed line shows the 2025 milestone of the End TB Strategy, which is a 75% reduction in the total number of deaths caused by TB between 2015 and 2025. Indonesia is included in the WHO Western Pacific Region for the whole time series. a Deaths from TB among people with HIV are officially classified as deaths caused by HIV/AIDS in the International Classification of Diseases, with TB as a contributory cause.", "133. Main findings and messages then the resumption of declines starting in either 2022 or 2023, is evident in the WHO European, South-East Asia and Western Pacific regions. In the WHO Eastern Mediterranean Region, an increase in 2020 and 2021 was followed by a decline in 2022 and then by a small increase between 2022 and 2024. In the WHO Region of the Americas, the estimated number of deaths caused by TB peaked in 2022, declined in 2023 and stabilized in 2024. In the WHO African Region, the estimated num - ber of deaths caused by TB has fallen year on year since 2011. Patterns in the 30 high TB burden countries vary, but most had a declining or flat trend between 2023 and 2024.1 In 2024, 69% of the global number of deaths caused by TB among HIV-negative people occurred in the WHO African and South-East Asia regions; India alone accounted for 28% of deaths globally. The WHO African and South-East Asia regions accounted for 71% of the combined total number of deaths caused by TB among people with and without HIV; India accounted for 25% of such deaths. Of the global number of deaths caused by TB among HIV-negative people in 2024, an estimated 537 000 (95% UI: 368 000\u2013705 000) were adult men (aged \u226515 years), equivalent to 50% of the total; 372 000 (95% UI: 243 000\u2013502 000) were adult women (aged \u226515 years), equivalent to 34% of the total; and 172 000 (95% UI: 107 000\u2013236 000) were children and young adolescents (aged <15 years), equivalent to 16% of the total. Of the global deaths from TB among people with HIV, an estimated 78 000 (95% UI: 39 000\u2013116 000) were adult men (51.9% of the total), 70 000 (95% UI: 26 000\u2013113 000) were adult women (46.6% of the total) and 2300 (95% UI: 1600\u20132900) were children and young adolescents (1.5% of the total). Progress towards milestones and targets for reducing TB disease burden Mostly off track, some success stories The first End TB Strategy milestones for reductions in TB disease burden were a 35% reduction in the total number of deaths caused by TB (including those among people with HIV 2) and a 20% reduction in the TB inci - dence rate by 2020, compared with levels in 2015; the second milestones, for 2025, were a 75% reduction in deaths from TB and", "a 50% reduction in the TB incidence rate (Box 2 ). The 2030 targets are an 80% reduction in the TB incidence rate and a 90% reduction in the num - ber of TB deaths, compared with 2015. The 2025 milestones are far away globally and in most 1 Time series for each of the 30 high TB burden countries are displayed in graphics provided on the report webpages and in the report app. 2 Officially classified as deaths from HIV/AIDS, with TB as a contributory cause. parts of the world, with reversals of progress during the COVID-19 pandemic making them much harder to achieve. Nonetheless, large reductions in TB incidence and mortality have been achieved in some regions and countries. Globally, the net reduction in the TB incidence rate from 2015 to 2024 was 12% \u2013 about one quarter of the way to the End TB Strategy milestone of a 50% reduc - tion by 2025 (Fig. 1 , right panel). At the level of WHO regions, progress in reducing the TB incidence rate since 2015 varies considerably (Fig. 2 ). Two WHO regions have made substantial progress: the European Region, with a net reduction of 39% by 2024; and the African Region, with a reduction of 28%. 3 There were smaller net declines in two other WHO regions: South-East Asia (16%) and the Eastern Mediterranean (5.9%). In the two other WHO regions, there were net increases of 1.7% in the Western Pacific and 13% in the Region of the Americas.4 Progress in reducing the TB incidence rate at coun - try level is highly variable ( Fig. 13 ). By 2024, a total of 101 countries, mostly in the WHO African and European regions, had achieved estimated reductions of at least 20% since 2015, thus reaching or surpassing the first (2020) milestone of the End TB Strategy, albeit with a delay of up to 4 years ( Table 3 ).5 A total of 30 countries are estimated to have achieved reductions of at least 50% between 2015 and 2024, surpassing the 2025 mile - stone of the End TB Strategy. At the other extreme, there are 37 countries where the TB incidence rate in 2024 was estimated to be more than 5% higher than in 2015. Many of these countries are in the WHO Region of the Americas, but they also include three high TB burden countries in", "Asia: Indonesia, Myanmar and the Philippines. Globally, the net reduction in the total number of deaths caused by TB between 2015 and 2024 was 29% (Fig. 9 , left panel), still far from the 2025 milestone of a 75% reduction. At the level of WHO regions, as with reductions in TB incidence rates, progress in achieving reductions in the number of deaths caused by TB since 2015 var - ies ( Fig. 12 ). Two WHO regions have made substantial progress: the European Region, with a net reduction of 49% by 2024; and the African Region, with a reduction of 46%.6 Following major reversals of progress during the COVID-19 pandemic, the net decline by 2024 compared with 2015 was 23% in the WHO South-East Asia Region, 3 These are the only regions to have surpassed the first milestone of the End TB Strategy. 4 Estimates of changes in TB incidence and mortality since 2015 in the WHO South-East Asia and Western Pacific regions differ from those published in previous reports, following the reassignment of Indonesia to the Western Pacific Region (see above). 5 The analysis here is restricted to countries (excluding \u201careas\u201d). 6 These are the only regions to have surpassed the first milestone of the End TB Strategy.", "14 Global tuberculosis report 2025 FIG. 13 Change (%) in the estimated TB incidence rate (new cases per 100 000 population per year) at country level, 2024 compared with 2015 The first milestone of the End TB Strategy was a 20% reduction by 2020, compared with 2015; the second milestone is a 50% reduction by 2025, compared with 2015. The last two categories (decrease 20\u201349%, and decrease \u226550%) distinguish the countries that have made the most progress towards the second milestone of the End TB Strategy. Change (2024 vs 2015, %) Increase (>5%) Stable (\u20135% to +5%) Decrease (6\u20139%) Decrease (10\u201319%) Decrease (20\u201349%) Decrease (\u226550%) No data Not applicable Change (2024 vs 2015, %) Increase (>5%) Stable (\u20135% to +5%) Decrease (6\u201319%) Decrease (20\u201334%) Decrease (35\u201349%) Decrease (\u226550%) No data Not applicable FIG. 14 Change (%) in the estimated number of deaths caused by TB among HIV-negative people and people with HIV at country level, 2024 compared with 2015 The first milestone of the End TB Strategy was a 35% reduction by 2020, compared with 2015; the second milestone is a 75% reduction by 2025, compared with 2015. The last two categories (decrease 35\u201349%, and decrease \u226550%) distinguish the countries that have made the most progress towards the second milestone of the End TB Strategy.", "15 3.8% in the Eastern Mediterranean Region and 1.2% in the Western Pacific Region. In the WHO Region of the Americas, the estimated number of deaths caused by TB in 2024 was much higher than in 2015 (+16%). Nonethe - less, the absolute number of deaths in 2024 remained small (about 30 000) while the TB mortality rate was comparable to that in the WHO European Region and much lower than in the other four WHO regions.1 Progress in reducing the number of deaths caused by TB at country level is highly variable ( Fig. 14 ). By 2024, a total of 65 countries had achieved net reductions of at least 35% since 2015, thus reaching or surpassing the first (2020) milestone of the End TB Strategy, albeit with a delay of up to 4 years ( Table 3 ). These countries are mostly in the WHO African and European regions. Several high TB burden countries in the WHO African Region have achieved reductions of 50% or more (e.g. Kenya, Nigeria, Uganda, the United Republic of Tanzania and Zambia). In the WHO European Region, one of the global TB watchlist countries (the Russian Federation) has achieved a reduction of 61%.2 At the other extreme, there are 45 countries where the number of deaths caused by TB in 2024 was more than 5% above the level of 2015, most noticeably in the WHO Region of the Amer- icas. A total of 49 countries reached both of the first mile - stones of the End TB Strategy between 2020 and 2024 (Table 3 ). Estimation of TB disease burden Repeat surveys and strengthened surveillance needed for 2030 targets assessment Data sources used to produce estimates of TB inci - dence in the period 2010\u20132024 include results from population-based surveys of the prevalence of TB dis - ease (used for 29 countries that account for about two thirds of global TB incidence), results from national TB inventory studies (used for 10 countries that collectively account for about 18% of global TB incidence), 3 mortal- ity data (used for 1 country that accounts for 1.0% of global TB incidence), case notification data (available for all countries) and values of the UHC SCI (available 1 The TB mortality rate among HIV-negative people in the WHO Region of the Americas was 2.1 per 100 000 population in 2024, compared with 25 in the African Region, 1.6", "in the European Region, 10 in the Eastern Mediterranean Region, 24 in the South- East Asia Region and 9.5 in the Western Pacific Region. 2 Alongside the list of 30 high TB burden countries for 2021\u20132025, WHO established a global TB watchlist ( Annex 3 ). The watchlist comprises the three countries that transitioned out of the previous list for 2016\u20132020: Cambodia, the Russian Federation and Zimbabwe. 3 These measure the level of underreporting of people diagnosed with TB in official TB case notification data; if certain conditions are met, capture\u2013recapture methods can be used to estimate TB incidence. for almost all countries). 4 For 26 countries with the big - gest absolute reductions in TB notifications during the COVID-19 pandemic that were a clear departure from historic trends, estimates of TB incidence in 2020\u20132024 were based on these data sources in combination with country or region-specific dynamic models (14, 16, 17).5 The main data source used to produce estimates of TB mortality in the period 2010\u20132024 is cause-of-death data from national or sample vital registration (VR) sys - tems. These data are available for 123 countries that account for 55% of the global number of deaths caused by TB among HIV-negative people.6 In the years leading up to the 2030 target year of the End TB Strategy and SDG deadline, repeat national TB prevalence surveys, national TB inventory studies, up-to-date cause-of-death data from national or sample VR systems of high quality and coverage and improve - ments in the quality and coverage of TB notification data are needed to strengthen burden estimation, with the goal of ensuring that assessment of progress made between the baseline year of 2015 and the target year of 2030 is as robust as possible. WHO is coordinating glob - al efforts to achieve this goal, under the umbrella of the WHO Global Task Force on TB Impact Measurement (21, 22). There are two excellent examples of recent studies to measure TB disease burden. The first example is a repeat national TB inventory study that was completed in Indonesia in 2023. This showed a big reduction in the level of underreporting of people newly diagnosed with TB compared with the first study in 2017, and produced estimates of TB incidence for 2023 that were consistent with existing model-based estimates (23). The second example is a national TB prevalence survey that was implemented in Cambodia in", "2023. Cambodia is the first country to complete three national TB prevalence surveys in the 21st century (after previ - ous surveys in 2002 and 2011) and the first to complete a survey after the COVID-19 pandemic. The three surveys show reductions in TB prevalence of about 50% per dec- ade between 2002 and 2023 ( Fig. 15 ).7 As of September 2025, national TB inventory studies were in the planning stage in Mongolia, the Philippines, South Africa and Viet Nam. Twelve countries were actively interested in implementing a repeat national 4 Further details about the data sources and analytical methods used to produce estimates of TB incidence are provided in the report webpages (section 1.1) and a technical appendix. 5 These methods were explained in more detail in the 2022 and 2023 editions of this report (14, 17); see, in particular, Box 3 in the 2022 report and Box 4 of the 2023 report. 6 Further details about the data sources and analytical methods used to produce estimates of TB mortality are provided in the report webpages (section 1.2) and a technical appendix. 7 The 2023\u20132024 national TB prevalence survey in Cambodia is one of the featured topics of the report webpages; the topic describes, illustrates and discusses the main survey results and lessons learned. 3. Main findings and messages", "16 Global tuberculosis report 2025 TABLE 3 Countries that reached the first End TB Strategy milestones for reductions in TB incidence and mortality between 2020 and 2024, by WHO region. The first milestones were a 20% reduction in the TB incidence rate and a 35% reduction in the number of TB deaths, compared with levels in 2015; the milestones were initially set for 2020 ( Box 2). The year in which the milestone was reached is shown. *Countries in WHO\u2019s list of 30 high TB burden countries, and three global TB watchlist countries ( Annex 3). COUNTRY INCIDENCE MORTALITY AFRICAN REGION Total number of countries 27 26 Algeria 2020 Benin 2020 2022 Botswana 2020 2022 Burkina Faso 2024 Burundi 2020 2022 Cabo Verde 2020 Cameroon 2020 2022 Central African Republic* 2022 Chad 2022 2023 Comoros 2021 2024 C\u00f4te d\u2019Ivoire 2020 2021 Democratic Republic of the Congo* 2022 Equatorial Guinea 2022 Eritrea 2020 Eswatini 2020 2020 Ethiopia* 2020 2024 Gabon* 2022 Gambia 2024 Ghana 2024 Kenya* 2020 2020 Lesotho* 2020 Liberia* 2022 2020 Malawi 2020 2020 Mauritania 2020 2022 Mozambique* 2020 Namibia* 2020 Nigeria* 2022 Rwanda 2022 S\u00e3o Tom\u00e9 and Principe 2020 2020 Senegal 2024 Sierra Leone* 2023 South Africa* 2020 South Sudan 2020 Togo 2020 Uganda* 2021 United Republic of Tanzania* 2020 2020 Zambia* 2021 2021 REGION OF THE AMERICAS Total number of countries 11 7 Antigua and Barbuda 2020 2021 Dominica 2020 2020 Dominican Republic 2020 Grenada 2020 2020 Guyana 2020 Haiti 2020 2023 Honduras 2020 Jamaica 2020 2020 Nicaragua 2020 Saint Kitts and Nevis 2020 Saint Lucia 2020 2020 Saint Vincent and the Grenadines 2020 EASTERN MEDITERRANEAN REGION Total number of countries 11 1 Bahrain 2020 Djibouti 2020 Egypt 2023 Iran (Islamic Republic of) 2020 Iraq 2020 Jordan 2021 Kuwait 2020 Saudi Arabia 2020 Sudan 2020 2020 Tunisia 2022 United Arab Emirates 2021 COUNTRY INCIDENCE MORTALITY EUROPEAN REGION Total number of countries 40 21 Armenia 2020 2020 Austria 2020 2020 Azerbaijan 2020 Belarus 2020 2020 Belgium 2023 2020 Bosnia and Herzegovina 2020 2020 Bulgaria 2020 Croatia 2020 Denmark 2020 2020 Estonia 2020 2020 Finland 2020 Georgia 2020 2020 Germany 2020 Greece 2021 Hungary 2020 Iceland 2020 Ireland 2020 Israel 2020 Italy 2020 Kazakhstan 2020 2023 Kyrgyzstan 2020 Latvia 2020 2020 Lithuania 2020 2020 Montenegro 2024 Netherlands (Kingdom of the) 2020 North Macedonia 2020 Norway 2020 2022 Poland 2020 Portugal 2020 2024 Republic of Moldova 2020 Romania 2020 Russian", "Federation* 2020 2020 Serbia 2020 2020 Slovakia 2020 Slovenia 2020 2020 Spain 2020 Sweden 2020 Switzerland 2020 Tajikistan 2020 T\u00fcrkiye 2020 Turkmenistan 2020 Ukraine 2020 2020 Uzbekistan 2021 2020 SOUTH-EAST ASIA REGION Total number of countries 3 1 Bhutan 2020 2021 India* 2024 Maldives 2020 WESTERN PACIFIC REGION Total number of countries 9 9 China* 2024 Japan 2020 2023 Lao People\u2019s Democratic Republic 2021 2020 Marshall Islands 2024 Palau 2020 2020 Republic of Korea 2020 2020 Samoa 2020 2020 Singapore 2020 Solomon Islands 2020 Tonga 2020 2020 Vanuatu 2020 2020", "173. Main findings and messages TB prevalence survey: Ethiopia, Ghana, Malawi, Nige - ria, Uganda, the United Republic of Tanzania, Zambia and Zimbabwe in Africa; and Bangladesh, Indonesia, Pakistan and Thailand in Asia. 1 In Nigeria, an innova - tive approach to survey design and implementation is in the advanced stages of development. This involves leveraging existing staff, laboratory infrastructure and other resources that have already been established for large-scale community and health-facility-based active case-finding, and nesting 1\u20132 subnational surveys with - in the national survey. As part of the follow-up to the September 2024 meeting of the WHO Global Task Force on TB Impact Measurement (22), a global priority list for national TB prevalence surveys in the years up to 2030 is in develop- ment, based on consultations with Member States and partner agencies. TB case notifications Small increase globally Globally in 2024, 8.3 million people were newly diag - nosed with TB and officially notified as a TB case, similar to the level of 8.2 million in 2023 and 17% higher than the pre-pandemic level of 7.1 million in 2019 ( Fig. 16 ). Explanations for the high numbers of TB case notifica - tions in 3 consecutive years (2022\u20132024) include a strong post-COVID recovery in the provision of and access to TB diagnosis and treatment, a backlog of people with TB whose diagnosis was delayed by the pandemic and a rise in the overall number of people developing TB disease ( Fig. 1 ) due to increased trans mission result - ing from diagnostic delays. They follow serious COVID-related disruptions to TB-related health services in 2020 and 2021, when the reported numbers of peo - 1 Further details are provided in the report webpages (section 1.4). ple newly diagnosed with TB fell considerably below pre-pandemic levels, to 5.8 million in 2020 and 6.4 mil - lion in 2021. At the level of WHO regions, recent trends (since the pre-pandemic year of 2019) in TB case notifications vary (Fig. 17 ). The pattern in the WHO Eastern Mediterranean and South-East Asia regions was similar to the global trend, with a big reduction in 2020 followed by year- on-year increases from 2021\u20132024 (the South-East Asia Region drove the global trend). In the WHO Region of the Americas, the European Region and the Western Pacific Region, notifications also fell sharply in 2020 and increased from 2021 to 2023, but then", "fell in 2024. The WHO African Region was the striking exception to these trends; notifications fell only slightly in 2020 and subsequently increased, particularly between 2021 and 2023, before levelling off in 2024. In 2024, the reported number of people newly diagnosed with TB in the WHO African Region was 38% above the level of 2019. In most of the 30 high TB burden countries, case noti- fications fell in 2020 and have subsequently recovered to the pre-pandemic (2019) level or beyond. The excep - tions to this general pattern are three countries where notifications increased throughout the period 2019\u2013 2024 (the Central African Republic, the Democratic Republic of the Congo and Nigeria), two countries where a long-term historic decline pre-2020 continued large - ly uninterrupted (China and the Democratic People\u2019s Republic of Korea) and Ethiopia, where a relatively con - sistent decline for several years has been reversed since 2021 (possibly reflecting active case-finding efforts). 2 2 Further details are provided in the report webpages (section 2.1). FIG. 16 Global trend in case notifications of people newly diagnosed with TB ( black) and the estimated number of incident TB cases (green), 2010\u20132024 The shaded area represents the 95% uncertainty interval. 2010 2015 2020 2024 0 5 10 15 Millions per year a Estimates are based on the case definitions used in each survey. FIG. 15 Prevalence of bacteriologically confirmed pulmonary TB among people aged \u226515 years in Cambodia, as measured a in three national TB prevalence surveys: 2002, 2011, 2023 2002 2005 2008 2011 2014 2017 2020 2023 0 500 1000 1500Prevalence per 100 000 population 2000", "18 Global tuberculosis report 2025 Diagnostic testing for TB Coverage of rapid testing improving but much more needed An essential step in the pathway of TB care is rapid and accurate diagnostic testing. Since 2011, rapid molecular tests have transformed the TB diagnostic landscape, which previously relied upon more traditional micros - copy and culture methods. People diagnosed with TB using WHO-recommend - ed rapid diagnostic tests (WRDs) (24), lateral flow urine lipoarabinomannan (LF-LAM) assays, sputum smear microscopy or culture are defined as \u201cbacteriologi - cally confirmed\u201d cases of TB (25). The microbiological detection of TB is critical because it allows people to be correctly diagnosed and ensures that the most effective treatment regimen (depending on the pattern of drug resistance) can be selected as early as possible. The use of rapid tests is growing but remains much too limited and falls far short of the target of 100% cov - erage by 2027 (Fig. 18 , Table 1 ). Globally in 2024, a WRD was used as the initial diag - nostic test for 54% (4.5 million) of the 8.3 million people newly diagnosed with TB, an improvement from 48% FIG. 17 Trends in the number of people newly diagnosed with TB and officially notified as a TB case (black) and the estimated number of incident TB cases ( green) by WHO region, 2010\u20132024 Shaded areas represent 95% uncertainty intervals. Indonesia is included in the WHO Western Pacific Region for the whole time series.Millions per year 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 0 1 2 3 4 0 0.1 0.2 0.3 0.4 0 2 4 6 8 0 0.2 0.4 0.6 0 0.3 0.6 0.9 1.2 0 1 2 3 4 African Region Region of the Americas Eastern Mediterranean RegionEuropean Region South-East Asia Region Western Pacific Region (3.9/8.2 million) in 2023 and 47% (3.5/7.5 million) in 2022. There was substantial variation in the coverage of rapid testing among regions and countries in 2024 (Fig. 18 , Fig. 19 ). Among WHO regions, the best level of coverage was achieved in the European Region (77%) and the West - ern Pacific Region (70%); the lowest coverage was in the South-East Asia Region (41%). At country level, 69 countries achieved coverage lev - els of at least 80% in 2024. This included seven high TB burden countries: the Central African Republic, China, Mongolia, Mozambique, Namibia,", "Uganda and Zambia. Among the 49 countries in one of the three global lists of high-burden countries (for TB, HIV-associated TB and MDR/RR-TB),1 37 reported that a WRD had been used as the initial test for more than half of people newly diag - nosed with TB in 2024 \u2013 up from 31 in 2023. Coverage of rapid testing was less than 20% in 21 countries. A major influence on the coverage of rapid testing is the proportion of TB diagnostic sites with access to WRDs. In 2024, only eight of the 30 high TB burden coun- tries reported that more than 50% of their TB diagnostic 1 See Annex 3 .", "19 3. Main findings and messages FIG. 18 Percentage of people newly diagnosed with TB who were initially tested with a WHO-recommended rapid diagnostic test (WRD), globally and for WHO regions, 2015\u20132024 a Indonesia is included in the WHO Western Pacific Region for the whole time series.Percentage 0 25 50 75 100 2015 2018 2021 2024 2015 2018 2021 2024 0 25 50 75 100 2015 2018 2021 2024 2015 2018 2021 2024 African Region Region of the Americas Eastern Mediterranean RegionEuropean Region South-East Asia Region Western Pacific Region Global a Data are for notified cases. FIG. 19 Percentage of people newly diagnosed with TB who were initially tested with a WHO-recommended rapid diagnostic test (WRD) at country level, a 2024 a Data are for notified cases. Percentage (%) <20 20\u201339 40\u201359 60\u201379 \u226580 No data Not applicable", "20 Global tuberculosis report 2025 sites had access to WRDs: Bangladesh, China, Lesotho, Mongolia, Namibia, Papua New Guinea, South Africa and Zambia. This list was unchanged from 2023. Expanding access to TB diagnosis using rapid tests should be a top priority for all countries. Reductions in the price of rapid tests would facilitate such expansion. In many countries, there is a need to increase the per- centage of people diagnosed with pulmonary TB based on bacteriological confirmation, including by ensuring that all those diagnosed with TB are initially tested with a rapid test, in line with the global target set for 2027 (Table 1 ). Of the 6.9 million people diagnosed with pulmonary TB worldwide in 2024, 64% were bacteriologically con - firmed (Fig. 20 ), a small improvement from 62% in 2023. Among the six WHO regions, there were steady improvements between 2020 and 2024 in the African Region (from 65% to 70%) and the Region of the Amer - icas (from 77% to 81%); in the other regions, levels of bacteriological confirmation were either stable or fell slightly (Fig. 19 ). At country level, the percentage of people with pul - monary TB who were bacteriologically confirmed was 80% or more in 114 countries. Among the 30 high TB burden countries, six achieved a level of 75% or above: Bangladesh, Liberia, Mongolia, Namibia, Nigeria and Viet Nam. The levels of bacteriological confirmation already achieved in the WHO Region of the Americas and in a variety of countries in other parts of the world show what is feasible with currently available TB diagnostics. Efforts to reach comparable levels, particularly through expanded use of rapid tests, are required elsewhere. 1 Testing for HIV among people diagnosed with TB High levels of coverage sustained The global coverage of HIV testing among people diag - nosed with TB remained high in 2024, at 82%. This was a slight increase from 81% in 2023 and 80% in 2022. At regional level, the highest percentages were achieved in the WHO African Region (89%) and the Euro- pean Region (94%). In 101 countries or areas, at least 90% of people diagnosed with TB knew their HIV status; this included 32 of the 47 countries in the WHO African Region, where the burden of HIV-associated TB is high - est. Worldwide in 2024, a total of 413 516 cases of TB among people living with HIV", "were notified, equivalent to 6.2% of the 6.7 million people newly diagnosed with TB who had an HIV test result. Overall, the percentage of people newly diagnosed with TB who had an HIV-posi - 1 Further details (e.g. for individual countries) are provided in the report webpages (section 2.2) and the report app. FIG. 20 Percentage of people newly diagnosed with pulmonary TB who were bacteriologically confirmed, globally and for WHO regions, a 2010\u20132024 Indonesia is included in the WHO Western Pacific Region for the whole time series.Percentage 0 20 40 60 80 100 0 20 40 60 80 100 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 African Region Region of the Americas Eastern Mediterranean RegionEuropean Region South-East Asia Region Western Pacific Region Global a Data are for notified cases. The calculation for years prior to 2013 is based on smear results, except for the European Region where data on confirmation by culture were also available for the period 2010\u20132012.", "21 tive test result has been falling globally for many years, following a peak of 28% in 2006. Coverage of TB diagnosis and treatment Post-COVID recovery sustained but sizeable gaps remain The 2025 milestone and 2030/2035 targets of the End TB Strategy can only be achieved if everyone who develops TB disease is promptly diagnosed using WHO-recom - mended diagnostic tests and then treated with drug regimens recommended by WHO (24, 26, 27).1 One of the targets set at the 2023 UN high-level meeting on TB is that 90% of people with TB have access to quality-as - sured diagnosis and treatment by 2027 (Table 1 ). There are still sizeable global and regional gaps between the estimated number of people who develop TB each year (incident cases) and the number of people newly diagnosed with TB and officially reported as a TB case (Fig. 16 , Fig. 17). In 2024, the best estimate of the global gap was 2.4 million. 2 The gap has narrowed since 2020, a year in which it widened substantially (to a best estimate of 4.5 million) amid COVID-related disruptions in the first year of the pandemic. Gaps have also been narrowing in five WHO regions, most notably in the WHO African, Eastern Mediterranean and South-East Asia regions. The exception is the Region of the Americas. Reasons for gaps between the estimated number of people who develop TB each year (incident cases) and the number of people newly diagnosed with TB and officially reported as a TB case include underdiagnosis as well as underreporting of people diagnosed with TB to national authorities (with the latter not accounted for in official case notification data). It is also important to highlight that some of the people diagnosed with TB and officially reported as a TB case may not have had the disease. Overdiagnosis is most likely to occur among people who have TB signs and symptoms but who have a bacteriologically negative test result. Universal coverage of the most sensitive and specific WHO-rec - ommended diagnostics for all people with presumptive TB is needed to limit the number of overdiagnoses. The global number of people newly diagnosed with TB and officially reported as a TB case in 2024 (8.3 mil - lion) was equivalent to 78% (95% UI: 72\u201384%) of the estimated 10.7 million (95% UI: 9.9\u201311.5 million) people who developed TB in 2024. This was a", "slight increase from 76% (95% UI: 71\u201382%) in 2023 and was consider - ably higher than the levels of 49% (95% UI: 40\u201363%) in 2010 and 57% (95% UI: 53\u201361%) in 2020. Among the 30 high TB burden countries in 2024, the number of people newly diagnosed with TB and 1 A summary of the treatment regimens recommended by WHO is provided in Annex 1 . 2 That is, the difference between a best estimate of 10.7 million incident cases and 8.3 million people who were newly diagnosed with TB and officially notified as a TB case. officially reported as a TB case as a percentage of the estimated number of people who developed TB (inci - dent cases) was highest (>80%) in Bangladesh, Brazil, Ethiopia, India, Kenya, Mozambique, Uganda and Zam - bia.3 In Mozambique especially, overdiagnosis may have artificially inflated notification data, given that the proportion of notified cases diagnosed based on bacte - riological confirmation in 2024 was only 50%. Three high TB burden countries had particularly low numbers of people newly diagnosed with TB relative to estimated levels of incidence in 2024: Lesotho (about 50%), Mongolia (<50%) and Myanmar (<50%). In 2024, the global gap between estimated TB incidence and the reported number of people new - ly diagnosed with TB was mostly accounted for by 10 countries ( Fig. 21 ). These 10 countries collectively accounted for 63% of the global gap. The top five coun - tries (collectively accounting for 40% of the global gap) were Indonesia (10%), India (8.8%), the Philippines (7.5%), Pakistan (7.2%) and China (6.9%). From a global perspective, efforts to increase levels of case detection and treatment are of particular importance in these countries. ART for people living with HIV and TB High coverage, scope for further progress Among people living with HIV who develop TB, both TB treatment and ART for HIV are required to prevent unnecessary deaths from TB and HIV. Since 2019, the global coverage of ART for people living with HIV who were newly diagnosed with TB and reported as a TB case has been maintained at a high level; it reached 91% in 2024, up from 88% in 2023. However, when provision of ART is compared with the total number of people living with HIV estimated to have developed TB in 2024, coverage was much lower, at 61%. This was almost unchanged from the level", "of 60% in 2023, and far below the overall level of ART cov - erage for people living with HIV, which was 77% (95% UI: 62\u201390%) at the end of 2024 (28). The main reason for the relatively low coverage was the big gap between the estimated number of people living with HIV who developed TB in 2024 (a best estimate of 619 000) and the reported number of people living with HIV who were diagnosed with TB in 2024 (413 516). TB treatment outcomes Sustained at high levels The treatment success rate for people treated for drug-susceptible TB has been sustained at a high lev - el in recent years. Globally, it was 88% in 2023 and in 2022 \u2013 an increase from 87% in 2021 and 86% in 2020 (Fig. 22 ). Treatment success rates remain lower among peo - 3 Further details are provided in the report webpages (section 2.3). 3. Main findings and messages", "22 Global tuberculosis report 2025 ple living with HIV (79% globally in 2023, unchanged from 2022). The treatment success rate for children and young adolescents (aged <15 years) was 92% in 2023, an increase from 90% in 2022. Among 31 high burden coun- tries1 that reported outcome data disaggregated by sex, the treatment success rate in 2023 was slightly higher among females (90%) than males (87%). Provision of TB treatment to HIV-negative people is estimated to have averted 45 million deaths between 2010 and 2024; among people living with HIV who were diagnosed with TB, the combination of TB treatment and ART is estimated to have averted an additional 7.0 million deaths between 2010 and 2024 (Table 4 ). The combined total for the period 2000\u20132024 was 83 million. Drug-resistant TB: diagnosis and treatment Diagnostic gaps, improving treatment outcomes, growing use of 6-month regimens WHO uses five categories to classify cases of drug- resistant TB: \u25b6 isoniazid-resistant TB; \u25b6 RR-TB (defined above); \u25b6 MDR-TB (defined above); \u25b6 pre-extensively drug-resistant TB (pre-XDR-TB), 1 Since 2021, WHO has requested data on treatment outcomes disaggregated by sex from the 49 countries in one of the three WHO lists of high burden countries, which are for TB, HIV- associated TB and MDR/RR-TB ( Annex 3 ). The countries from which such data are requested may be expanded in future (e.g. to include all countries with case-based digital surveillance systems for TB). Nigeria Democratic Republic of the Congo Pakistan India China Bangladesh Viet Nam Philippines Indonesia FIG. 21 The ten countries with the largest gaps between notifications of people newly diagnosed with TB and the best estimates of TB incidence, a 2024 a The ten countries ranked in order of the size of the gap between notified cases and the best estimates of TB incidence in 2024 are Indonesia, India, the Philippines, Pakistan, China, Myanmar, the Democratic Republic of the Congo, Nigeria, Viet Nam and Bangladesh. Size of gap 50 000 150 000 250 000 Myanmar FIG. 22 Global treatment success rates for drug- susceptible TB and MDR/RR-TB, 2012\u20132023 a Year started on treatment People treated for drug-susceptible TB People treated for MDR/RR-TB 50 60 70 80 90 100 Treatment success rate (%) 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 a 2012 is the first year for which WHO collected data about treatment outcomes for MDR/RR-TB.", "23 TABLE 4 Cumulative number of deaths (in millions) averted by a) TB treatment as well as b) antiretroviral treatment for people diagnosed with TB who were also living with HIV, globally and by WHO region, 2010\u20132024 Indonesia is included in the WHO Western Pacific Region. HIV-NEGATIVE PEOPLE PEOPLE LIVING WITH HIV\u1d43 TOTAL WHO REGION BEST ESTIMATE UNCERTAINTY INTERVAL BEST ESTIMATE UNCERTAINTY INTERVAL BEST ESTIMATE UNCERTAINTY INTERVAL African Region 6.6 5.4\u20137.7 5.2 4.4\u20136.0 12 10\u201313 Region of the Americas 1.5 1.4\u20131.6 0.27 0.24\u20130.29 1.8 1.6\u20131.9 South-East Asia Region 17 14\u201319 0.85 0.52\u20131.2 18 15\u201320 European Region 1.3 1.2\u20131.5 0.25 0.22\u20130.28 1.6 1.4\u20131.7 Eastern Mediterranean Region 4.2 3.6\u20134.7 0.056 0.024\u20130.088 4.2 3.7\u20134.8 Western Pacific Region 14 13\u201316 0.42 0.34\u20130.50 15 13\u201316 Global 45 40\u201350 7 6.0\u20137.9 52 46\u201357 a Deaths from TB among people with HIV are officially classified as deaths caused by HIV/AIDS (with TB as a contributory cause). This is the reason why the estimates make a clear distinction between people with and without HIV. defined as TB that is resistant to rifampicin and any fluoroquinolone (a class of second-line anti-TB drug); and \u25b6 XDR-TB, defined as TB that is resistant to rifampicin, plus any fluoroquinolone, plus at least one of either bedaquiline or linezolid. RR-TB is included in WHO\u2019s Bacterial Priority Pathogens List, where it sits within the \u201ccritical group\u201d category (29).1 Detection of drug resistance requires bacteriologi - cal confirmation of TB and testing for resistance using rapid molecular diagnostic tests, culture methods or sequencing technologies. Since 2018, WHO has recommended all-oral regimens for the treatment of MDR/RR-TB (30). The latest recom - mendations for treatment of drug-resistant TB include three major categories of regimen (26, 27): \u25b6 two 6-month all-oral regimens for people with MDR/ RR-TB (with or without resistance to fluoroquinolo - nes);2 \u25b6 several all-oral short regimens of 9 months for peo - ple with MDR/RR-TB who do not have any resistance to fluoroquinolones; and \u25b6 longer regimens of 18\u201320 months that may include an injectable drug (amikacin). The 6-month regimens are prioritized for use whereas the longest regimens are a last resort. 1 The list includes 15 pathogens. Four are in the \u201ccritical group\u201d, seven are in the \u201chigh group\u201d and four are in the \u201cmedium group\u201d. 2 One regimen, referred to as BPaLM, comprises bedaquiline, pretomanid, linezolid and moxifloxacin. The other regimen, referred to as BDLLfxC, comprises bedaquiline, delamanid and linezolid, combined", "with levofloxacin or clofazimine or both. Unlike BPaLM, the latter can be used in children and during pregnancy. Globally in 2024, 83% of people diagnosed with bac - teriologically confirmed TB were tested for rifampicin resistance (3.7/4.5 million), up from 79% (3.4/4.3 million) in 2023, representing major progress compared with 69% (2.4/3.5 million) in 2021 and 62% (2.2/3.6 million) in the pre-pandemic year of 2019 ( Fig. 23 ). There were improvements in all six WHO regions; in 2024, the best coverage was in the European Region (91%), the South- East Asia Region (90%) and the Western Pacific Region (89%). Of the 30 high MDR/RR-TB burden countries, 24 reached a coverage of at least 80% in 2024: Angola, Azer- baijan, Bangladesh, Belarus, China, India, Indonesia, Kazakhstan, Kyrgyzstan, Mongolia, Myanmar, Nigeria, Papua New Guinea, Peru, the Republic of Moldova, the Russian Federation, Somalia, South Africa, Tajikistan, Ukraine, Uzbekistan, Viet Nam, Zambia and Zimbabwe. Three high MDR/RR-TB burden countries did not reach a coverage level of 50%: the Democratic People\u2019s Republic of Korea (1.6%), the Democratic Republic of the Congo (35%) and Mozambique (31%). Among those tested for RR-TB worldwide in 2024, 147 592 people with MDR/RR-TB and 25 140 people with pre-XDR-TB or XDR-TB were detected, giving a com - bined total of 172 732 (4.6% of those tested). This was a decrease (\u20138.9%) from a combined total of 189 631 in 2023. Despite increased testing coverage and an increase in the absolute number of people tested, the number of people detected with MDR/RR-TB was lower in 2024 than in 2019 (when the total was 202 009). This is consistent with the estimated decline in the proportion of people with TB who have MDR/RR-TB (Fig. 7 ). Worldwide, 164 545 people with MDR/RR-TB were enrolled on treatment in 2024, a fall (of 7.0%) from 177 017 in 2023 ( Fig. 24 ). This level of enrolment is equivalent to 42% of the estimated number of people 3. Main findings and messages", "24 Global tuberculosis report 2025 who developed MDR/RR-TB in 2024, similar to the level of 43% in 2023 (Fig. 6 , Fig. 24 ). Five countries accounted for about 60% of the gap between the estimated global number of people who developed MDR/RR-TB in 2024 (incident cases of MDR/ RR-TB) and the global number of people enrolled on treatment in 2024. Listed in order of their share of the global gap, these countries were India (33%), the Phil - ippines (9.3%), Indonesia (7.3%), China (6.1%) and Pakistan (4.1%). Closing the global and country-level gaps between the estimated number of people developing MDR/ RR-TB each year and the number of people started on treatment for MDR/RR-TB each year requires further improvements in the coverage of testing for RR-TB among those with bacteriologically confirmed TB, improvements in the percentage of those diagnosed with TB who are bacteriologically confirmed (necessary to test for drug resistance) and improvements in the proportion of people with TB who are diagnosed. In recent years, there has been considerable progress in the treatment success rate achieved among people diagnosed with MDR/RR-TB (Fig. 22 ). For people started on treatment in 2022 (the latest year for which outcome data are available),1 the treatment success rate was 71% \u2013 up from 68% in 2021 and 64% in 2020, and much better 1 The time lag is because some treatment regimens last 18\u201320 months. FIG. 23 Percentage of people diagnosed with bacteriologically confirmed TB who were tested for rifampicin-resistant TB (RR-TB a), globally and for WHO regions, 2010\u20132024 Indonesia is included in the WHO Western Pacific Region for the whole time series. Percentage 0 20 40 60 80 100 0 20 40 60 80 100 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 2010 2015 2020 2024 African Region Region of the Americas Eastern Mediterranean RegionEuropean Region South-East Asia Region Western Pacific Region Global a Includes both new and previously treated cases; data for 2017 onwards are for pulmonary cases only. FIG. 24 Global number of people diagnosed with MDR/RR-TB ( blue) and number enrolled on an MDR-TB treatment regimen ( red), compared with estimates of the global number of incident cases of MDR/RR-TB (95% uncertainty interval shown in green), 2015\u20132024 a a The time period corresponds to the period for which estimates of the incidence of MDR/RR-TB are available. 2015 2016 2017 2018 2019 2020 2021", "25 than the level of 50% in 2012.1 Among WHO regions, the treatment success rate in 2022 ranged from 60% in the Region of the Americas to 77% in the South-East Asia Region. Globally, the use of 6-month treatment regimens is expanding. In 2024, 34 256 people with MDR/RR-TB were reported to have been started on treatment with 6-month regimens, a substantial increase from 5653 in 2023 and 1744 in 2022. By the end of 2024, 6-month reg- imens were being used for treatment of MDR/RR-TB in 97 countries, up from 60 at the end of 2023 and 41 at the end of 2022. Longer regimens (18\u201320 months) remain the most widely used of the three major categories of regimen. In 2024, 54% of people with MDR/RR-TB were enrolled on treatment with longer regimens, followed by 9-month (21%) and 6-month (21%) regimens.2 At regional level, the percentage of people treated for MDR/RR-TB with 6-month regimens increased sub - stantially between 2023 and 2024 in the WHO African, Eastern Mediterranean and Western Pacific regions. The percentages in 2024 were highest in the WHO African Region (45%) and the Eastern Mediterranean Region (57%). TB prevention and screening Global coverage of TPT improving The main health care intervention available to reduce the risk of TB infection progressing to active TB disease is TPT. Other preventive interventions are TB infection prevention and control, and vaccination of children with the bacille Calmette-Gu\u00e9rin (BCG) vaccine. The BCG vac- cine can confer protection, especially from severe forms of TB in children. WHO recommends TPT for people living with HIV, household contacts of people diagnosed with bacterio - logically confirmed pulmonary TB and people in clinical risk groups (e.g. those receiving dialysis) (31).3 Options include a weekly dose of isoniazid and rifapentine for 3 months, a daily dose of isoniazid and rifampicin for 3 months, a daily dose of isoniazid and rifapentine for 1 month, a daily dose of rifampicin for 4 months and a daily dose of isoniazid for 6 or 9 months. In people exposed to MDR/RR-TB, a daily dose of levofloxacin for 6 months is recommended. The global number of people provided with TPT in 2024 was 5.3 million, a further increase from 4.7 million in 2023 and a more than fivefold improvement com - pared with 2015 (Fig. 25 ).4 Since 2021, there has been a particularly noticeable 1 2012 was the first year", "for which WHO collected data on outcomes for people enrolled on treatment for MDR/RR-TB. 2 For 4% of people, the regimen type was not reported. 3 Addressing broader determinants that influence TB epidemics can also help to prevent TB infection and disease. These are discussed below. 4 The number in 2015 was 1.0 million. increase in the number of household contacts enrolled on TPT: from 0.76 million in 2021 to 3.5 million in 2024. In contrast, the number of people living with HIV who were enrolled on TPT increased between 2015 and 2019 (reaching a peak of 3.0 million in 2019) before falling in 2020 and subsequently levelling off at about 2 million people per year. The estimated global coverage of TPT among house - hold contacts reached 25% in 2024, up from 20% in 2023 and substantially better than levels achieved in 2015 (<1%) and 2019 (5.0%) ( Fig. 26 ).5 For people liv - ing with HIV, coverage among those newly enrolled on ART was higher, at 58%; this was a small increase from 56% in 2023. The global target of 90% coverage by 2027 (Table 1 ) remains some way off. In 95 countries that reported outcomes, the median completion rate for household contacts who started 5 Region and country-specific data are provided in the report webpages (section 3) and the report app. People living with HIV Household contacts aged <5 years Household contacts aged \u22655 years 0 1 2 3 4 5 6 Number of people (millions) 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 FIG. 25 Global number of people provided with TPT, 2015\u20132024 People living with HIV who were newly initiated on ART Household contacts of people newly diagnosed with TB Target for 2027 set at the 2023 UN high-level meeting on TB 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 0 20 40 60 80 100 Percentage started on treatment FIG. 26 Global coverage of TPT, 2015\u20132024 3. Main findings and messages", "26 Global tuberculosis report 2025 TPT in 2023 was 89%, up from 87% (in 85 countries) in 2022. For people living with HIV, the median completion rate in 38 countries that reported data was 84% in 2023, up from 81% in 42 countries that reported data for 2022. Substantial intensification and expansion of efforts and investment are needed to improve the provision of TPT. This includes providing more TB screening at household level, improving the follow-up to TB screen - ing at household level and among people living with HIV, and increasing access to shorter (1\u20133 months) rifamycin-based regimens. The number of people treat - ed using shorter regimens is growing; in 2024, it reached 2.1 million people (44% of those who started TPT) in 88 countries, 1 more than double the total of 1.0 million people in 86 countries in 2023 and a tenfold increase from 0.19 million people in 52 countries in 2021. The ratio of the TB notification rate among health care workers to the TB notification rate in the general adult population reflects the effectiveness of TB infec - tion control in health facilities; the ratio should be about 1. In 2024 the ratio was greater than 1 in nine countries that reported five or more TB cases among health care workers; this was a slight reduction from 12 countries in 2023 and 14 countries in both 2022 and 2021. The global coverage of BCG vaccination in children was 88% in 2024, similar to the levels achieved in 2023 (87%) and 2022 (88%) after concerning declines (to 86% in 2020 and 85% in 2021) during the COVID-19 pandemic (32). Funding for TB services Stagnating globally and far from target Cuts to international donor funding threaten progress Progress in reducing the burden of TB disease requires adequate funding for TB prevention, diagnostic and treatment services, sustained over many years. Howev - er, in low- and middle-income countries (LMICs) \u2013 which account for 99% of the reported number of people new- ly diagnosed with TB each year \u2013 funding has stagnated for 5 years and in 2024 it remained far short of what is needed. Cuts to international donor funding for the TB response in 2025 now threaten the sustainability of cur - rent levels of TB prevention, diagnostic and treatment services, and have made domestic funding in high TB burden countries more important than ever. In 2024,", "the total funding available in LMICs was US$ 5.9 billion (in constant 2024 US$), 2 equivalent to 1 Among these 88 countries, 82 reported using the 3-month weekly regimen of rifapentine and isoniazid, and 28 reported using the 1-month daily regimen of rifapentine and isoniazid. Overall, these two regimens were used for 73% of those treated using rifamycin- based regimens. 2 All amounts quoted in this subsection are in constant 2024 US$. Numbers should not be directly compared with those in previous reports, because adjustments to the whole time series are made for each new report, to account for inflation. only 27% of the global target of reaching US$ 22 billion per year by 2027 ( Fig. 27 , Table 1 ). The level of funding has stagnated since 2020, hovering around US$ 6 billion per year. Throughout the period 2015\u20132024, the share of fund - ing available from domestic and international sources in LMICs was relatively consistent. In 2024, 82% of the funding available for TB prevention, diagnostic and treatment services was from domestic sources. Inter - national donor funding amounted to US$ 1.1 billion in 2024, having ranged from US$ 1.1 billion to US$ 1.2 bil - lion in almost every year since 2015, 3 with most of this funding provided through grants from the Global Fund and bilateral funding from USAID.4 In 2024, the overall figure for the share of funding pro- vided from domestic sources in LMICs continued to be strongly influenced by the five original BRICS countries: Brazil, the Russian Federation, 5 India, China and South 3 The exception was 2017, when it reached US$ 1.3 billion. 4 Further details are provided in the report webpages (section 4.1 and section 4.2). 5 In the most recent classification of countries by income group published by the World Bank (33), the Russian Federation was categorized as a high-income country. It has been included in analyses for LMICs because it was an upper-middle-income country for most of the period 2015\u20132024, it is in WHO\u2019s list of high-burden countries for drug-resistant TB and it is one of the three countries on WHO\u2019s global TB watchlist ( Annex 3 ). FIG. 27 Funding available for TB prevention, diagnostic and treatment services in 131 low- and middle-income countries by source, a,b,c 2015\u20132024 Total Domestic funding International donor funding 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 0 4 8", "12 16 20 24 Billions (constant 2024 US$) Target for 2027 set at the 2023 UN high-level meeting on TB a Sources: data reported by NTPs and estimates produced by the WHO Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections. b The data sources, boundaries, accounting rules, and estimation methods used in this report are different from those of the System of Health Accounts 2011 (SHA2011). The TB funding data reported here are thus not comparable with the disease expenditure data, including for TB, that are reported in WHO\u2019s Global Health Expenditure Database. c The 131 countries accounted for 99% of the global number of notified TB cases in 2024.", "27 Africa1 ( Fig. 28 ). Together, these countries accounted for US$ 3.1 billion (64%) of the total of US$ 4.8 billion in 2024 that was provided from domestic sources. Overall, 96% of available funding in BRICS and all funding in Bra- zil, China and the Russian Federation in 2024 was from domestic sources. In other LMICs, international donor funding remained crucial ( Fig. 28 ). In 2024, such funding accounted for 54% of the funding available in the 26 high TB burden countries and two global TB watchlist countries (Cam - bodia and Zimbabwe) outside BRICS, and 63% of the funding available in low-income countries. In 2025, decisions by the government of the United States of America (USG) and wider political develop - 1 BRICS is used here to refer only to the five original members of the BRICS group of countries, acknowledging that this group expanded in 2024 and in 2025 comprises 11 countries. ments have resulted in cuts to international donor funding, including for health in general and TB specifi - cally. In 2024, the USG was the largest contributor of fund - ing to the Global Fund (about one third). It was also the largest bilateral donor for TB, providing grants to 24 pri- ority countries. Through these two channels, the USG contributed about 50% of international donor funding for TB in the period 2015\u20132024. 2 In 2025, the Global Fund has anticipated reductions in contributions due to changes in the landscape of funding for global health, and requested countries to pause or defer activities as a first step. As of July 2025, 2 This figure is based on a comprehensive analysis of international donor funding for TB based on donor reports to the Organisation for Economic Co-operation and Development (OECD). A graphic that illustrates the shares contributed by OECD countries is provided in the report webpages (section 4.2). 3. Main findings and messages FIG. 28 Funding available for TB prevention, diagnostic and treatment services in 131 low- and middle- income countries and three other country groups, a,b 2015\u20132024 BRICS: Brazil, the Russian Federation, India, China, South Africa. a Sources: data reported by NTPs and estimates produced by the WHO Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections. b The data sources, boundaries, accounting rules, and estimation methods used in this report are different from those of the System of Health Accounts 2011 (SHA2011). The", "TB funding data reported here are thus not comparable with the disease expenditure data, including for TB, that are reported in WHO\u2019s Global Health Expenditure Database. c The 131 countries accounted for 99% of the global number of notified TB cases in 2024. d The two global TB watchlist countries included are Cambodia and Zimbabwe. Domestic funding International donor funding Billions (constant 2024 US$) Billions (constant 2024 US$) Billions (constant 2024 US$) Billions (constant 2024 US$) All low- and middle-income countriesc (n=131) BRICS (n=5) High TB burden and global TB watchlist countries outside BRICSd (n=28) Other low- and middle-income countries (n=98) 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 0 2 4 6 8 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 0 1 2 3 4 0 0.4 0.8 1.2 1.6 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 0 0.2 0.4 0.6 0.8 1 1.2 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024", "28 Global tuberculosis report 2025 funding for the 2024\u20132026 grant cycle had been cut by US$ 1.4 billion \u2013 equivalent to 11% of the original allo - cation (34). It remains too early for a reliable assessment of domestic and international donor funding for the TB response in 2025. 1 However, the share of national TB programme (NTP) funding in 2024 that was provided by bilateral grants from USAID, grants from the Glob - al Fund and domestic sources in countries that were USG priorities for TB provides a good indication of the extent to which changes to USG bilateral funding and reductions in grants from the Global Fund could impact overall levels of funding in 2025. In 2024, USG bilateral funding accounted for 20% or more of the total available funding reported by NTPs in 13 of the USG priority countries for TB, with the high - est share (over 30%) in Zambia and Cambodia ( Fig. 29 ). Almost all the countries that received USG bilateral funds for TB in 2024 were also highly reliant on Global Fund grants in 2024 (the main exception was India). Modelling has already been used to assess how cuts in international donor funding for TB in these countries and other LMICs could affect the number of people 1 Data about the total amount of funding available for the TB response in 2025, by funding source and category of expenditure, will be collected by WHO in the next (2026) round of global TB data collection ( Annex 2 ). developing TB and the number of deaths caused by TB (35\u201338). Estimates of impact include: \u25b6 about half a million additional deaths and 1.4 million additional cases 2 in the period 2025\u20132035 if USAID funding is not replaced, increasing to about 2 mil - lion additional deaths and 5 million additional cases when cuts in contributions to the Global Fund are also considered (36);3 \u25b6 about 0.1 million additional deaths and 0.6 million additional cases in the period 2025\u20132030 resulting from USG funding cuts, if service disruptions last for only 3 months and funding is subsequently restored, potentially increasing to about 2 million additional deaths and 10 million additional cases if USG funding is not restored (or replaced) and service disruptions are prolonged (37).4 For comparison, WHO has estimated that disruptions to TB diagnosis and treatment during the COVID-19 pan - demic resulted in", "about 700 000 excess TB deaths in the 4-year period 2020\u20132023 (23). 2 This is compared with a scenario in which levels of funding in 2024 are sustained. 3 These estimates are for 79 countries that collectively account for about 90% of global TB incidence. 4 These estimates are for 26 high TB burden countries that collectively account for about 80% of global TB incidence. FIG. 29 Sources of funding available a for TB prevention, diagnostic and treatment services in 2024, for 21 countries b that reported receiving Global Fund grants and bilateral funding from USAID in 2024 India Kyrgyzstan Ukraine Indonesia South Africa Afghanistan United Republic of Tanzania Democratic Republic of the Congo Zimbabwe Kenya Nigeria Uganda Tajikistan Mozambique Bangladesh Myanmar Philippines Ethiopia Malawi Cambodia Zambia 02 04 06 08 0 100 Percentage of available funding (%) USAID Global Fund Other international funding Domestic funding USAID: United States Agency for International Development. a Domestic funding in this graphic is based on data reported by NTPs, which typically do not include the financial costs associated with inpatient and outpatient care required during TB treatment. b There were an additional three countries that were USAID priorities for bilateral funding for TB in 2024 for which data were not available: Pakistan, Uzbekistan and Viet Nam.", "29 A key influence on model projections is the assump - tion that cuts in funding will result in a proportionate reduction in access to treatment.1 Given the potential impact of funding cuts on the numbers of people falling ill with TB and the number of deaths caused by TB, it is critical to monitor how TB services are being affected in practice. In 2025, WHO has gathered information from countries about how TB services and associated support systems are being affected, with particular attention to countries (shown in Fig. 29 ) that were recipients of both USG bilateral funding and Global Fund grants in 2024. WHO has also continued to request countries to report provisional TB case notification data on a monthly or quarterly basis (39), using a system initially established in 2020 to mon - itor the impact of COVID-related disruptions; these data can provide an early signal of whether disruptions to diagnosis and treatment are occurring. Again, particular attention has been given to countries that were recip - ients of both USG bilateral funding and Global Fund grants in 2024 (and this will continue). As of August 2025, the most frequently reported impacts on services and supportive systems were related to TB community engagement, TB screening, TB diagnosis, sample transportation and supply-chain management, with a moderate or severe impact reported by eight or more of the 17 countries for which information was provided; only a few countries reported that TB treatment services had been affected ( Fig. 30 ). In terms of NTPs specifically, more than half of the 17 countries reported impacts on technical support (e.g. from in-country advisors), management and super - 1 In the models, this is captured as a reduction in the per-capita rate of diagnosis and treatment initiation. vision activities, staffing, procurement of diagnostic supplies, periodic surveys (e.g. national TB prevalence surveys, national surveys of anti-TB drug resistance and national surveys of costs faced by TB-affected house - holds), programme reviews and the development of national strategic plans.2 Provisional monthly and quarterly TB case noti - fication data available for the first 6 months of 2025 suggest a mixed picture that will need ongoing attention (Fig. 31 ). The countries with reductions in notifications beyond what would be expected based on recent trends include Cambodia, Kenya, Mozambique and Uganda. In 2025, Nigeria and South Africa are two examples of high TB burden", "countries that have increased domes- tic funding for TB, to mitigate the loss of international donor funding. Variation in the share of funding from domestic sources within a given income group suggests that there is scope to increase domestic funding in some other high TB burden and global TB watchlist countries.3 Strong national strategic plans for TB that are prop - erly costed should provide the foundation for domestic resource mobilization; countries committed to such plans at the 2023 UN high-level meeting on TB (Table 2 ). WHO guidance on national strategic planning is availa - ble (40) and the TB module of the Integrated Health Tool for planning and costing (available online) can be used for budgeting as well as optimization of resource alloca- tion and use. 2 Further details are provided in one of the \u201cfeatured topics\u201d on the report webpages. 3 Further details are provided in the report webpages (section 4.1). 3. Main findings and messages FIG. 30 Reported impacts on TB services and associated support systems in 2025, for 17 countries a that reported receiving Global Fund grants and bilateral funding from USAID in 2024 a As of August 2025, information was not available for four of the 21 countries shown in Fig. 29 . Information was obtained from WHO country offices between April and August 2025. TB treatment Referral system TB patient support Data management systems TB diagnosis TB preventive treatment Supply chain management Sample transportation TB screening TB community engagement 02 46 81 01 21 41 6 Number of countries Severe impact Moderate impact Minimal or no impact", "30 Global tuberculosis report 2025 UHC and costs faced by TB-affected households Faster progress required, TB target off track Global targets for reductions in TB disease burden can only be achieved if TB prevention, diagnostic and treatment services are provided within the context of progress towards UHC. For example, when the End TB Strategy was adopted in 2014, it was estimated that reaching the 2025 milestone of a 75% reduction in the number of deaths caused by TB (compared with 2015) would require reducing the TB case fatality rate to 6.5% by 2025.1 Such a low case fatality rate is only feasible if everyone with TB can promptly access diagnostic and treatment services. UHC means that everyone can obtain the health services they need without suffering financial hardship (41). Through their adoption of the SDGs, all countries have committed to achieving UHC by 2030: Target 3.8 is \u201cAchieve universal health coverage, including financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all\u201d (1). The two indicators being used to monitor progress towards this target are a UHC SCI (Indicator 3.8.1) and the percentage of the population experiencing house - hold expenditures on health care that are \u201clarge\u201d in 1 This was in combination with a 50% reduction in the TB incidence rate. The estimated case fatality rate in 2024 was 11.5%. relation to household expenditures or income (Indica - tor 3.8.2). 2 The SCI can take values from 0 (worst) to 100 (best); to date, it has been calculated using 14 tracer indica - tors, one of which is the coverage of TB treatment. In the monitoring of Indicator 3.8.2 by WHO and the World Bank, direct out-of-pocket medical expenditures that account for more than 10% of annual household expenditure or income have been classified as \u201ccat - astrophic\u201d (41\u201343). As of September 2025, estimates of the SCI at global, regional and country levels were available for the period 2000\u20132021, while estimates of the percentage of the population facing catastrophic out-of-pocket health expenditures at global, regional and country-income-group levels were available for 2000\u20132019 (42, 43).3,4 Worldwide, the SCI increased from a score of 45 (out of 100) in 2000 to 68 in 2019, and remained stable at this level in 2021. Most progress occurred between 2000 and 2015, and was primarily due to improvements in service coverage", "for infectious diseases (with only 2 Indicator 3.8.2 is a measure of financial hardship rather than financial barriers to accessing health care. The need for out-of- pocket payments may deter many people from seeking care. 3 For this reason, estimates in this section are based on those published as of September 2025. 4 The definitions of SDG Indicator 3.8.1 and SDG Indicator 3.8.2 were updated in March 2025; updated estimates are scheduled for publication in December 2025. FIG. 31 Provisional number of case notifications of people newly diagnosed with TB in 2025 (relative to 2024) compared with the share of funding for TB that was provided by USAID bilateral grants in 2024, for 16 countries a that reported receiving Global Fund grants and bilateral funding from USAID in 2024 On the y-axis, values below 1 indicate fewer notifications in 2025 compared with 2024, and vice versa for values above 1. The comparison is for the first 6 months of 2024 and 2025. The horizontal dashed lines demarcate levels of +5% and -5%, relative to 2024. a Notification data reported to WHO as of 8 October 2025 were used. Of the 21 countries that reported relevant funding data ( Fig. 29 ), provisional notification data for 2025 were not available for Afghanistan, Kyrgyzstan, Malawi, Nigeria and Tajikistan. 10 20 30 0.75 1.00 1.25 1.50 Ratio of 2025 to 2024 case notifications Percentage of funding reported by NTPs that was provided by USAID bilateral grants in 2024 0.50 India Ukraine Indonesia South Africa Kenya Bangladesh Uganda Philippines Mozambique Myanmar Ethiopia Cambodia Zambia Democratic Republic of the Congo United Republic of Tanzania Zimbabwe", "31 limited changes for other areas of service provision). At regional level, the SCI increased in all six WHO regions between 2000 and 2019; the biggest gains in absolute terms were in the Eastern Mediterranean Region (from 30 to 62) and the Western Pacific Region (from 49 to 79). There were also increases in all four World Bank income groups. Progress stalled between 2019 and 2021 in most WHO regions and World Bank income groups. In 2021, the WHO regions with the highest values were the European Region (81) and the Region of the Americas (80); the region with the lowest value was the African Region (44). Among the 30 high TB burden countries, most made progress in service coverage between 2000 and 2019. The largest gains in absolute terms (+30 index points or more) were in China, India, Myanmar, Thailand and Viet Nam. However, as at global and regional levels, progress stalled or reversed in most countries between 2019 and 2021, during the COVID-19 pandemic. In 2021, the high TB burden countries with the highest SCI values (around 80) were Brazil, China and Thailand; most other countries had values between about 40 and 60 (Fig. 32 ). In contrast to improvements in the SCI, the proportion of the general population facing catastrophic out-of- pocket expenditures on health worsened between 2010 and 2019, rising from 11.4% (794 million people) in 2010 to 13.5% (1.04 billion people) in 2019 (42). At regional level, higher proportions in 2019 compared with 2010 were estimated for all WHO regions except the Region of the Americas. National values for the percentage of the popula - tion facing catastrophic out-of-pocket expenditures on health are available for different years and there is more geographical variability than with the SCI, includ - ing within regions. Of the 30 high TB burden countries, estimates of the percentage of the population facing catastrophic health expenditures are particularly high (\u226515% of the population) for Angola, Bangladesh, China, India, Nigeria, Sierra Leone and Uganda. Values for both indicators in the 30 high TB burden countries show that there is a long way to go before the SDG targets for UHC are achieved in most of these coun- tries (Fig. 32 ). Only Thailand stands out as having a very high SCI (82 in 2021)1 and a low level of catastrophic out- of-pocket health expenditures (2.0% of households). A Universal Coverage Scheme was", "established in Thai - land in 2002 to provide an explicit benefit to all citizens of the country who were not already covered by a health insurance scheme in the formal sector; the scheme is supported by domestic funding and a strong primary health care system (44). To achieve UHC, substantial increases in investment in health care are critical. Between 2000 and 2022, 2 1 Categories used by WHO for UHC SCI monitoring are \u201cvery high\u201d (\u226580), \u201chigh\u201d (60\u201379) and \u201cmedium\u201d (40\u201359). 2 2022 is the latest year for which data are currently available. there were striking increases in health expenditure (from all sources) per capita in a small number of high TB burden countries, notably the upper-middle-income countries of Brazil, China, South Africa and Thailand. There have also been considerable increases in sever - al lower-middle-income countries: Bangladesh, India, Indonesia, Kenya, Lesotho, Mongolia, Myanmar, the Philippines and Viet Nam. Health expenditure has been rising in most low-income and high TB burden coun - tries, most noticeably in the Central African Republic, Ethiopia, Liberia and Mozambique, albeit from much lower levels.3 Given the importance of UHC to targets for reduc - tions in TB incidence and mortality, the End TB Strategy included a third target for the reduction of cost barriers to accessing TB diagnosis and treatment that are faced by people with TB and their households ( Box 2 ). The target is that no TB-affected households face total costs (comprising direct medical expenditures, nonmedical expenditures and indirect costs such as income losses) that are catastrophic (defined as total costs exceeding 20% of annual household income). The key differences between this TB-specific indicator and the SDG UHC indicator for household expenditures on health care (Indicator 3.8.2) are explained in Box 3 . Between 2015 and August 2025, a total of 42 coun - tries completed a national survey of costs faced by people treated for TB and their households; among these 42 countries, 40 (including 20 of the 30 high TB burden countries and two of the three global TB watch - list countries) 4 have reported results. 5 In 2024, repeat surveys were completed in the Republic of Moldova and Viet Nam, and data collection for a repeat survey was underway in Brazil and the United Republic of Tanzania. The mean total cost (in constant US$ prices for 2024)6 incurred by people treated for TB and their house", "- holds ranged from US$ 78 (95% confidence interval [CI]: US$ 62\u201397) in the Gambia to US$ 3800 (95% CI: US$ 3040\u20134560) in Mongolia. The percentage of TB-affected households facing total costs that were catastrophic ranged from 13% (95% CI: 10\u201317%) in El Salvador to 92% (95% CI: 86\u201397%) in the Solomon Islands; the pooled average for all 40 countries, weighted for each country\u2019s number of noti - fied cases, was 47% (95% CI: 37\u201358%) ( Fig. 33 ).7 Among 37 countries that reported disaggregated data, the percentage facing catastrophic total costs was much higher for drug-resistant TB, with a pooled average of 82% (95% CI: 71\u201393%). Survey results have been used to inform approaches 3 Further details are provided in the report webpages (section 5.1). 4 See Annex 3 . 5 Results from surveys in Benin and China have not been reported to WHO. 6 All values were converted to a common year of prices (constant 2024 US$), to allow for fair comparisons among surveys. 7 Further details are provided in the report webpages (section 5.2). 3. Main findings and messages", "32 Global tuberculosis report 2025 to health financing, service delivery and social protec - tion that will reduce these costs (45, 46). They have also been used to produce model-based estimates of total costs faced by TB-affected households in other coun - tries (47). Multisectoral action and accountability Coverage of social protection inadequate Undernutrition and diabetes are leading TB determinants Achieving global targets for reductions in TB disease burden requires multisectoral action to help mitigate or remove barriers to accessing essential TB services and to address broader social determinants that influence TB transmission and susceptibility to development of disease. At the second UN high-level meeting on TB FIG. 32 UHC service coverage index (SDG Indicator 3.8.1) a and percentage of the general population facing catastrophic health expenditure (SDG Indicator 3.8.2), b 30 high TB burden countries, c stratified by income group d Percentage of the general population facing catastrophic health expenditure (SDG Indicator 3.8.2) Upper-middle-income Lower-middle-income Low-income UHC service coverage index (SDG Indicator 3.8.1) 20 40 60 80 20 40 60 80 20 40 60 80 0 20 40 0 20 40 0 20 40 30 10 30 10 30 10 Democratic Republic of the Congo Ethiopia Mozambique Sierra Leone Uganda Angola Bangladesh India Indonesia Kenya MongoliaMyanmarNigeria Pakistan Philippines Viet Nam Brazil China Gabon NamibiaS outh Africa Thailand Liberia United Republic of Tanzania Zambia Central African Republic Congo Lesotho a The service coverage index (SCI) can take values from 0 (worst) to 100 (best) and is calculated using 14 tracer indicators, one of which is the coverage of TB treatment. Values shown for the SCI are estimates for the latest year for which data for SDG Indicator 3.8.2 are available. Values for the SCI are based on interpolated points between available years over the 2000\u20132021 period. b Defined in 2017 as >10% of total household consumption or income. The latest available year (based on data published in 2023) ranges from 2007 to 2021 for the 30 high TB burden countries. c Data for SDG Indicator 3.8.2 were not available for the Democratic People\u2019s Republic of Korea and Papua New Guinea. d The classification is for the latest year for which data for SDG Indicator 3.8.2 are available. Source: Global Health Observatory ( https://www.who.int/data/gho ). in 2023, Member States adopted a target that every - one with TB should have access to a health and social benefits package by 2027 (", "Table 1) and committed to strengthening multisectoral action and accountability (Table 2 ), including through use of the WHO MAF-TB (48).1 Evidence about the coverage of social protection is available from the ILO. Although the data are for the gen- eral population rather than being specific to people with TB, they provide good evidence about overall levels of social protection, including in high TB burden countries. An estimated 52% of the world\u2019s population is covered by at least one social protection benefit (up from 43% 1 To support use of the MAF-TB at national level, WHO has published a checklist for a situational assessment, an operational guide and examples of best practices (49\u201351).", "33 Box 3. The difference between \u201ccatastrophic total costs\u201d for TB-affected households, and the SDG UHC indicator related to household expenditures on health care It is important to distinguish between SDG Indicator 3.8.2, \u201cthe proportion of the population with large household expenditures on health as a share of total household expenditure or income\u201d, and \u201cthe percentage of TB-affected households facing catastrophic total costs due to TB\u201d, which is an indicator within the WHO End TB Strategy. The SDG indicator is for the general population. Household expenditures on health are defined as direct expenditures on health by all household members who seek any type of care (preventive, curative, rehabilitative or long-term) for any type of disease, illness or health condition, in any type of setting (outpatient, inpatient or at home). They include both formal and informal expenditures. This indicator attempts to capture the impact of household expenditures on health on household ability to spend on other basic needs. The denominator of the total population includes many people who had no contact with the health system and thus had zero expenditures on health. Although these people did not experience financial hardship because of direct expenditures on health care, they may nonetheless have faced financial barriers to accessing health services that they needed. Hence, the SDG indicator cannot be used as a measure of financial barriers to access to health care. Due to the nature of the illness, people with TB and their households can face severe direct and indirect financial and economic costs. These pose barriers that can greatly affect their ability to access diagnosis and treatment, and to complete treatment successfully. Costs included in the TB-specific indicator include not only direct medical payments for diagnosis and treatment, but also direct nonmedical payments (e.g. for transport and lodging) and indirect costs (e.g. lost income). In contrast to SDG Indicator 3.8.2, the TB- specific indicator is restricted to a particular population: people diagnosed with TB who are users of health services that are part of NTP networks. Given these conceptual differences, the percentage of TB-affected households facing \u201ccatastrophic total costs\u201d (defined as direct and indirect costs that account for >20% of their annual household income) is expected to be much higher than the percentage of the general population facing catastrophic expenditures on health care. Hence, the two indicators cannot and should not be compared directly. 3. Main findings and messages in 2015),1 with", "considerable variation among countries (Fig. 34 ). Coverage is strongly related to income level, ranging from an average of 9.7% in low-income coun - tries to 86% in high-income countries. Among the 30 high TB burden countries, the percentage of the popu - lation covered by at least one social protection benefit varies from 3.1% in Uganda to 94% in Mongolia; in 19 of these countries, the percentage is below 50%. When country values for the percentage of peo - ple covered by at least one social protection benefit are weighted according to each country\u2019s share of the global number of people newly diagnosed with TB and officially notified as a TB case in 2024, the global aver - age is 44%. This weighted average provides a more \u201cTB sensitive\u201d global figure related to the coverage of social protection. In July 2025, the need for intensified efforts to improve levels of social protection was recognized by UN Member States in the \u201cSevilla Commitment\u201d (52). The commitment is to expand the fiscal space for social protection, with a view to increasing coverage by at least 2 percentage points per year in countries where social protection is not yet universal. Many new cases of TB are attributable to five risk factors: undernutrition, diabetes, alcohol use disorders, smoking (especially among men) and HIV infection 1 This estimate is based on data for the latest available year in each country, which ranges from 2019 to 2025. (Fig. 35 ) (53\u201356).2,3 Multisectoral action is needed to address these and other determinants of TB, such as gross domestic product (GDP) per capita ( Fig. 36 ) and poverty.4 The status of progress in strengthening multisec - toral accountability for the TB response at national level can be assessed using data that are available for three key elements of the MAF-TB: multisectoral reviews of progress in the TB response and associated recom - mendations for action, including representation from civil society and affected communities; production of an annual TB report, to inform high-level review; and engagement of different sectors of government in the TB response. In 2025, 90 countries reported that they had a multi - sectoral review mechanism in place, including 19 of the 30 high TB burden countries. These review mechanisms had representation from civil society and affected com - munities in 73 countries, including 19 of the 30 high TB burden countries. A total", "of 110 countries reported publishing an annu - 2 Sources of data used to produce estimates include journal articles (53\u201356) , the World Bank SDG database, the WHO GHO and the WHO World Health Data Hub. 3 Estimates have been revised upwards for diabetes, following the availability of more recent estimates of the prevalence of diabetes in the general population (57). 4 SDG targets and indicators that are associated with TB incidence are described in Annex 5 .", "34 Global tuberculosis report 2025 FIG. 33 Estimates of the percentage of people treated for TB and their households facing catastrophic total costs (mean and confidence intervals), a national surveys completed 2015\u20132025 b a Defined as direct medical expenditures, direct nonmedical expenditures and indirect costs (e.g. income losses) that sum to >20% of annual household income. This indicator is not the same as the SDG indicator for catastrophic health expenditures; see Box 3 for further explanation. b The percentages are shown for 40 national surveys that have been completed and for which data have been reported. Data were not available for China and the Republic of Moldova. Global Western Pacific Region South-East Asia Region Region of the Americas African Region El Salvador Lesotho Central African Republic Kenya Thailand Congo Cambodia Papua New Guinea Guatemala Benin Indonesia Gambia Bangladesh Fiji Philippines United Republic of Tanzania Dominican Republic Argentina Brazil Mali Nepal Colombia Guinea Uganda Burkina Faso South Africa Democratic Republic of the Congo Zambia Myanmar Viet Nam Lao People's Democratic Republic Ghana Somalia Mongolia Nigeria Niger Zimbabwe Timor-Leste Namibia Solomon Islands All forms of TB 02 55 07 5 100 Percentage al TB report on progress towards national TB-related targets and commitments, including 22 of the 30 high TB burden countries. Beyond the health sector, the most widely engaged sectors of government were education (42% of countries), defence (34%), justice (27%) and social devel- opment (25%). There is considerable scope to increase engagement in these key sectors and beyond. WHO also recommends that countries conduct MAF- TB baseline assessments, and then use the results to develop a MAF-TB implementation plan. In 2025, 60 countries reported that they had completed a MAF-TB baseline assessment and 64 reported that a MAF-TB implementation plan had been developed. A total of 31 countries, including 12 high TB burden countries, had all five core elements of the MAF-TB in place. That is, they had a multisectoral review mech - anism, engagement of civil society and affected communities in the review mechanism, an annual report, a baseline assessment and an implementation plan.1 In line with the global part of the MAF-TB and requests at the 2023 UN high-level meeting on TB (Table 2 ), WHO will continue to lead the coordination of global TB mon- itoring, reporting and review, and will provide technical support and guidance to countries and partners. This work will continue to be informed", "by the WHO Civil Soci- ety Task Force on TB. In 2024, WHO initiated work on how climate change affects the TB epidemic and progress in response efforts. Particular attention is being given to three path- ways through which climate change affects TB: food insecurity and undernutrition, displacement and migra- tion of populations, and disruption to health systems. An analytical framework and research agenda were published in 2025 (58). 1 Further details are provided in the report webpages (section 5.4).", "35 a Data were not available for the Congo, the Democratic People\u2019s Republic of Korea and Gabon. b Data are shown for World Bank income groups since income level is a key influence on social protection coverage. c The latest available year ranges from 2019 to 2025. Source: International Labour Organization. FIG. 34 Percentage of the population covered by at least one social protection benefit, 30 high TB burden countries, a four income groups and globally, b latest available year c 3. Main findings and messages Mongolia China Brazil Thailand India South Africa Indonesia Namibia Viet Nam Philippines Zambia Bangladesh Pakistan Nigeria Lesotho United Republic of Tanzania Papua New Guinea Kenya Angola Ethiopia Myanmar Liberia Mozambique Democratic Republic of the Congo Sierra Leone Central African Republic Uganda High-income countries Upper-middle-income countries Lower-middle-income countries Low-income countries Global 02 04 06 08 0 100 Percentage 0.2 0.4 0.81 .0 Number of cases (millions) Undernutrition HIV infection Alcohol use disorders Diabetes Smoking 0 1.20.6 FIG. 35 Global estimates of the number of people with a new episode of TB (incident cases) attributable to five risk factors, a 2024 a Estimates for diabetes, smoking and alcohol use disorders are for the adult population only; this is consistent with available prevalence data. For adults aged \u226518, undernutrition is defined as a body mass index (BMI) <18.5. For children and adolescents aged 5\u201317 years, it is defined as a BMI of less than minus 2 standard deviations below the median. For those aged <5 years, it is defined as wasting (weight for height of less than minus 2 standard deviations from the median).", "36 Global tuberculosis report 2025 FIG. 36 Relationship between two SDG-related indicators a,b and the TB incidence rate Each dot represents a country or area. a The year of data used for GDP per capita and the population prevalence of undernutrition is the latest year for which data are available from the World Bank (https://data.worldbank.org/) and in the WHO Global Health Observatory (https://www.who.int/data/gho), respectively. b For adults aged \u226518, undernutrition is defined as a body mass index (BMI) <18.5. For children and adolescents aged 5\u201317, it is defined as a BMI of less than minus 2 standard deviations below the median. For those aged <5 years, it is defined as wasting (weight for height of less than minus 2 standard deviations from the median). TB research Pipelines expanding but changes in funding landscape threaten progress The End TB Strategy targets set for 2030 ( Box 2 ) cannot be met without intensified research and innovation (12). Major technological breakthroughs are urgently needed to accelerate the annual decline in the global TB incidence rate. Reductions in TB incidence achieved between 2015 and 2024 fall far short of the 2025 mile - stone of the strategy (12% compared with 50%). Priorities include new vaccines to reduce the risk of infection, new vaccines or preventive drug treatments to reduce the risk of TB disease in people already infected; rapid diagnostic tests for accurate detection of TB disease at the point of care; and simpler, shorter treatments for TB disease. WHO has developed a glob - al strategy for TB research and innovation, which was adopted by all Member States in 2020 (59). This aims to support accelerated TB research and innovation, and improve equitable access to the benefits of research. Recent years have seen important progress in the development of new TB diagnostics, drugs and vac - cines.1 1 A high-level summary is provided in this subsection. Further details are provided in the report webpages (section 6). The diagnostic pipeline has expanded considerably. In August 2025, there were 63 tests in development for diagnosis of TB disease and infection. For TB disease, they included point-of-care (POC) tests (e.g. lateral flow tests), near-POC nucleic acid amplification tests (NAATs), automated NAATs of both low and moderate complexi - ty, line probe assays for detection of drug resistance and targeted next-generation sequencing. For TB infection, they included interferon-gamma release assays and TB antigen-based skin tests. Novel", "technologies for TB screening (e.g. computer-aided detection using digital chest radiography) among people with a high likelihood of having TB disease were also in the pipeline. As of August 2025, there were 29 drugs for the treat - ment of TB disease in Phase 1, Phase 2 or Phase 3 trials. This is the same number as in 2024, but an impressive increase from only eight drugs in 2015. The 29 drugs comprise: \u25b6 18 new chemical entities: alphibectir (BVL-GSK098), BTZ-043, delpazolid, GSK-286, ganfeborole (GSK-3036656), macozinone, MK-7762 (TBD09), quabodepistat (OPC-167832), TBAJ-587, TBAJ-876, TBI-223, pyrifazimine (TBI-166), TBA-7371, telacebec (Q203), sanfetrinem, SQ109, sutezolid and sudapyri - dine (WX-081); 1 10 100 1000Incidence per 100 000 population in 2024 (log scale) 1 10 100 1000 11 01 00 GDP per capita (US$ thousands) 0.31 .0 30.0 Prevalence of undernutrition (Percentage of general population aged \u226518 years) 10.03.0 Incidence per 100 000 population in 2024 (log scale)", "37 \u25b6 three drugs that have already been approved by WHO for use in treatment: bedaquiline, delamanid and pretomanid; and \u25b6 eight repurposed drugs: clofazimine, levofloxacin, linezolid, moxifloxacin, rifampicin (high dose), rifap - entine, sitafloxacin and tedizolid. In addition, various combination regimens with new or repurposed drugs, as well as host-directed therapies, are in Phase 2 or Phase 3/4 trials, or are being evaluated as part of operational research projects. In August 2025, there were at least 42 clinical trials and implementation research studies underway to evaluate drug regimens and models of delivery for TPT. Trials are being used to assess the safety and efficacy of delama - nid in preventing MDR-TB, TPT in people with diabetes and novel short-course regimens (e.g. thrice-weekly isoniazid and rifapentine for 1 month and rifamycin monotherapies given over 6 or 8 weeks). At least 16 studies of novel delivery models in both community and facility-based settings are being implemented. In August 2025, there were 18 vaccine candidates in clinical trials, up from 15 in 2024: four in Phase 1, eight in Phase 2 and six in Phase 3. They included candidates to prevent TB infection and TB disease, and to help improve the outcomes of treatment for TB disease. Effective vaccines are particularly critical for accelerat - ing annual reductions in TB incidence to levels that are much faster than those achieved historically. Progress to date has been constrained by the overall level of investment. The most recently published data (60) show a total of US$ 1.2 billion in 2023 ( Fig. 37 ); this represents a modest increase from US$ 1.0 billion in 2022 but is still only 24% of the global target of US$ 5 bil- lion per year by 2027 (Table 1 ). FIG. 37 Funding for TB research, 2015\u20132023 Source: Treatment Action Group, Stop TB Partnership. Tuberculosis research funding trends 2005\u20132023. New York: Treatment Action Group; 2024 (https://www.treatmentactiongroup.org/resources/tbrd-report/tbrd- report-2024/ ) Target for 2027 set at the 2023 UN high-level meeting on TB 2015 2016 2017 2018 2019 2020 2021 2022 2023 0 1 2 3 4 5 6 Billions (current US$) Even these levels of investment are now at risk. In 2023, the public sector was the largest source of funding for TB research (62% of the total), followed by philan - thropic organizations (24%), the private sector (9%) and multilateral agencies (4%). Of particular significance, the US National Institutes", "of Health (NIH) was the largest individual funder, providing 34% of all global TB research funding. In 2025, many NIH grants for health-related research were terminated (61) and a 40% reduction in the NIH budget for 2026 has been proposed (62). When new evidence related to new TB drugs, diag - nostic tests, treatment regimens and vaccines becomes available, it is reviewed by WHO and used to update WHO recommendations related to TB prevention, diag - nosis, treatment and care (Box 4 ). Box 4. New WHO guidance related to TB prevention, diagnosis, treatment and care WHO published new guidelines and handbooks on TB prevention, diagnosis, treatment and care in the period between November 2024 and October 2025: \u25b6 consolidated guidelines and an operational handbook on TB diagnosis, which bring together guidance on detection of TB infection, disease and drug resistance in single documents (24, 63); \u25b6 consolidated guidelines and an operational handbook on TB treatment and care, which bring together guidance for drug-susceptible TB and drug- resistant TB that was previously provided separately and include new guidance on treatment of MDR/RR- TB based on evidence from recent trials (26, 64); and \u25b6 a third edition of an operational handbook on TB and comorbidities, which includes a new section on diabetes (65). Guidance on evidence generation related to new TB treatment regimens was released in December 2024 (66). A policy statement on the use of computer-aided detection for TB screening was issued in June 2025 (67). Target product profiles for TB screening tests and a consensus statement on the inclusion of pregnant and lactating women in TB research were released in August 2025 (68, 69). New recommendations on TB and undernutrition were published in October 2025 (70), as part of a second edition of consolidated guidelines on TB and comorbidities. All WHO guidelines and operational handbooks, as well as training modules and other documents to support the production of evidence-based recommendations, can be found on the WHO TB Knowledge Sharing Platform (71). 3. Main findings and messages", "38 Global tuberculosis report 2025 4. Conclusions All WHO and UN Member States have committed to end- ing the global TB epidemic, through their adoption of the End TB Strategy and SDGs. The 2030 targets of the End TB Strategy are a 90% reduction in the number of deaths caused by TB and an 80% reduction in the TB incidence rate compared with levels in 2015; the 2025 milestones are reductions of 75% and 50%, respective - ly. These commitments were reaffirmed at two UN high-level meetings on TB, held in 2018 and 2023, and reinforced with additional targets related to funding, the provision of treatment to people with TB disease or TB infection, and the availability of new TB vaccines. TB remains a major global public health problem, and progress in reducing the burden of disease falls far short of 2030 targets in most parts of the world. None - theless, after setbacks during the COVID-19 pandemic, most indicators are moving in the right direction and there are regional and country success stories. Further and faster reductions in the burden of TB disease require improvements in the coverage of TB diagnostic, treatment and preventive interventions; action on broader determinants that drive new infec - tions or increase the risk of developing disease once infected; and technological breakthroughs, such as a new TB vaccine. All depend on adequate funding, which remains grossly inadequate and has been stagnating since 2020. Cuts to international donor funding from 2025 onwards threaten overall funding for the TB response in many countries. To achieve the goal of ending the global TB epidemic, political commitment and domestic fund - ing in high TB burden countries are more important than ever.", "39 References 1. Sustainable Development Goals [website]. United Nations; 2024 ( https://sdgs.un.org/ ). 2. Global strategy and targets for tuberculosis prevention, care and control after 2015 (Resolution WHA67.1, Agenda item 12.1). 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Consolidated guidance on tuberculosis data generation and use: module 4: surveys of costs faced by households affected by tuberculosis. Geneva: World Health Organization; 2025 ( https://iris.who.int/handle/10665/381505 ). Licence: CC BY-NC- SA 3.0 IGO.", "41 47. Portnoy A, Yamanaka T, Nguhiu P , Nishikiori N, Garcia Baena I, Floyd K et al. Costs incurred by people receiving tuberculosis treatment in low-income and middle-income countries: a meta-regression analysis. Lancet Glob Health. 2023;11(10):e1640-e7 (https://doi.org/10.1016/S2214-109X(23)00369-8 ). 48. Multisectoral accountability framework to accelerate progress to end tuberculosis by 2030. Geneva: World Health Organization; 2019 (https://iris.who.int/handle/10665/331934 ). Licence: CC BY-NC-SA 3.0 IGO. 49. WHO Multisectoral accountability framework for TB (MAF-TB): baseline assessment checklist for country use in pursuing a national MAF-TB. Geneva: World Health Organization; 2020 (https://www.who.int/publications/m/item/who-multisectoral-accountability-framework-for-tb-(maf-tb)-baseline- assessment-checklist-for-country-use-in-pursuing-a-national-maf-tb ). Licence: CC BY-NC-SA 3.0 IGO. 50. Adaptation and implementation of the WHO Multisectoral accountability framework to end TB: operational guidance. Geneva: World Health Organization; 2023 ( https://iris.who.int/handle/10665/373901 ). Licence: CC BY-NC-SA 3.0 IGO. 51. Adaptation and implementation of WHO\u2019s Multisectoral accountability framework to end TB (MAF-TB): best practices. Geneva: World Health Organization; 2022 ( https://iris.who.int/handle/10665/365806 ). Licence: CC BY-NC-SA 3.0 IGO. 52. Sevilla Commitment. Fourth International Conference on Financing for Development, Seville, Spain, 2025 [website]. United Nations Digital Library; 2025 ( https://digitallibrary.un.org/record/4085602 ). 53. Imtiaz S, Shield KD, Roerecke M, Samokhvalov AV, Lonnroth K, Rehm J. Alcohol consumption as a risk factor for tuberculosis: meta-analyses and burden of disease. Eur Respir J. 2017;50(1) (https://doi.org/10.1183/13993003.00216-2017 ). 54. Hayashi S, Chandramohan D. Risk of active tuberculosis among people with diabetes mellitus: systematic review and meta-analysis. Trop Med Int Health. 2018;23(10):1058-70 ( https://doi.org/10.1111/tmi.13133). 55. Lonnroth K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P et al. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet. 2010;375(9728):1814-29 (https://doi.org/10.1016/S0140-6736(10)60483-7 ). 56. Franco JV, Bongaerts B, Metzendorf MI, Risso A, Guo Y, Pena Silva L et al. Undernutrition as a risk factor for tuberculosis disease. Cochrane Database Syst Rev. 2024;6(6):CD015890 ( https://doi.org/10.1002/14651858.CD015890.pub2 ). 57. N.C.D. Risk Factor Collaboration. Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants. Lancet. 2024;404(10467):2077-93 (https://doi.org/10.1016/S0140-6736(24)02317-1). 58. Saunders MJ, Boccia D, Khan PY, Gosce L, Gasparrini A, Clark RA et al. Climate change and tuberculosis: an analytical framework. medRxiv. 2025 ( https://doi.org/10.1101/2025.02.18.25322451 ). 59. Global Strategy for Tuberculosis Research and Innovation (WHA73.3). Seventy-third World Health Assembly. Geneva: World Health Assembly; 2020 ( https://apps.who.int/gb/ebwha/pdf_files/WHA73/A73_R3-en.pdf ). 60. Treatment Action Group, Stop TB Partnership. Tuberculosis research funding trends 2005\u20132023. New York: Treatment Action Group; 2024 (https://www.treatmentactiongroup.org/resources/tbrd-report/tbrd-report-2024/ ). 61. NIH scientists speak out over estimated $12 billion in Trump", "funding cuts [website]. Reuters; 2025 (https://www.reuters.com/business/healthcare-pharmaceuticals/nih-scientists-speak-out-over-estimated-12-billion- trump-funding-cuts-2025-06-09/ ). 62. FY 2026 Budget in Brief. Washington, D.C.: U.S. Department of Health and Human Services; 2025 (https://www.hhs.gov/sites/default/files/fy-2026-budget-in-brief.pdf ). 63. WHO operational handbook on tuberculosis: module 3: diagnosis. Geneva: World Health Organization; 2025 (https://iris.who.int/handle/10665/382121 ). Licence: CC BY-NC-SA 3.0 IGO. 64. WHO operational handbook on tuberculosis: module 4: treatment and care. Geneva: World Health Organization; 2025 (https://iris.who.int/handle/10665/359147 ). Licence: CC BY-NC-SA 3.0 IGO. 65. WHO operational handbook on tuberculosis: module 6: tuberculosis and comorbidities, 3rd edition. Geneva: World Health Organization; 2025 ( https://iris.who.int/handle/10665/380063 ). Licence: CC BY-NC-SA 3.0 IGO. 66. Guidance on evidence generation on new regimens for tuberculosis treatment. Geneva: World Health Organization; 2024 (https://iris.who.int/handle/10665/379830 ). Licence: CC BY-NC-SA 3.0 IGO. 67. Use of computer-aided detection software for tuberculosis screening: WHO policy statement. Geneva: World Health Organization; 2025 ( https://iris.who.int/handle/10665/381613 ). Licence: CC BY-NC-SA 3.0 IGO. 68. Optimal and early inclusion of pregnant and lactating women in tuberculosis research: consensus statement. Geneva: World Health Organization; 2025 ( https://iris.who.int/handle/10665/381875 ). Licence: CC BY-NC-SA 3.0 IGO. 69. Target product profiles for tuberculosis screening tests. Geneva: World Health Organization; 2025 (https://iris.who.int/handle/10665/382179 ). Licence: CC BY-NC-SA 3.0 IGO. 70. WHO consolidated guidelines on tuberculosis: module 6: tuberculosis and comorbidities, 2nd ed. Geneva: World Health Organization; 2025 ( https://iris.who.int/handle/10665/382883 ). Licence: CC BY-NC-SA 3.0 IGO. 71. WHO TB Knowledge Sharing Platform [website]. World Health Organization; 2025 (https://extranet.who.int/tbknowledge ). References", "43 ANNEX 1 Basic facts about TB Tuberculosis (TB) is an old disease. Studies of human skeletons show that it has affected humans for thou - sands of years (1). Its cause remained unknown until 24 March 1882, when Dr Robert Koch announced his dis - covery of the bacillus responsible, subsequently named Mycobacterium tuberculosis (2). The disease is spread when people who are sick with TB expel bacteria into the air (e.g. by coughing). TB typically affects the lungs (pulmonary TB) but can also affect other sites (extrapul- monary TB). Most people who develop the disease (about 90%) are adults and there are more cases among men than women. Diagnostic tests for TB disease have improved sub - stantially in recent years. There are now several rapid molecular tests recommended by WHO as the initial diagnostic test for TB, some of which can detect drug resistance simultaneously (3). These tests can be used at the lower levels of the health system. A point-of-care lateral-flow test performed on urine is also recommend- ed by WHO; its main use is to assist with diagnosis of TB in people with advanced HIV disease, in combination with rapid molecular tests. There are additional rapid molecular tests specifically for the detection of resist - ance to a variety of first- and second-line anti-TB drugs, while sequencing technologies can be used to provide a comprehensive individual profile of drug resistance. The older method of sputum smear microscopy (devel - oped >100 years ago) is still used for TB diagnosis in low and middle-income countries but is increasingly being replaced with rapid tests. Culture testing remains the reference standard for TB diagnosis. In addition, culture is required for the detec - tion of resistance to newer anti-TB drugs and may also be used as a confirmatory test in settings and situations in which people have a low pre-test probability of hav - ing TB disease. Following diagnosis, culture or smear (as opposed to rapid molecular tests) are necessary to monitor an individual\u2019s response to treatment. Screening can be used to detect people with TB ear - lier in the course of the disease, including people with TB whose diagnosis might otherwise be missed. TB screening algorithms recommended by WHO are based on chest X-ray, computer-aided detection software, molecular diagnostic tests, symptoms, physical signs and other tools (4). Without treatment, the death rate from TB is high.", "Studies of the natural history of TB disease in the absence of treatment with anti-TB drugs (conducted before drug treatments became available) found that about 70% of individuals with sputum smear-positive pulmonary TB died within 10 years of being diagnosed, as did about 20% of people with culture-positive (but smear-negative) pulmonary TB (5). Effective drug treatments were first developed in the 1940s. For people with drug-susceptible TB (both pulmo - nary and extrapulmonary), the latest WHO treatment guidelines (6) include a strong recommendation for a 6-month regimen of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z): all four drugs for the first two months, followed by H and R for the remaining 4 months. The guidelines also include recom- mendations that people aged 12 years and older with drug-susceptible pulmonary TB may be treated with a 4-month regimen of rifapentine (P), H, Z and moxiflox - acin (M), and that children and adolescents between 3 months and 16 years of age with non-severe TB (and without suspicion or evidence of resistance to R and H) may be treated with a 4-month regimen (2 months of H, R, Z and sometimes also E, followed by 2 months of H and R). Globally, the treatment success rate for people with drug-susceptible TB has been sustained at a high level for many years. In the latest annual cohort of peo - ple enrolled on treatment for which data are available (2023), it was 88%. Treatment for people diagnosed with R-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB, defined as resistance to H and R) requires other drug regimens. The latest WHO treatment guidelines (5) prioritize two 6-month regimens. One of these consists of bedaqui - line (B), pretomanid (Pa), linezolid (L) and M (BPaLM); it was approved by WHO in 2022. The second consists of B, delamanid (DL), L, levofloxacin (Lfx) and clofazimine (BDLLfxC); it was approved by WHO in 2024. Globally, the treatment success rate for RR-TB has been steadi - ly improving. It reached 71% in the most recent annual cohort of people enrolled on treatment for which data are available (2022), up from 50% in 2012. Further improvements are expected as the use of the 6-month treatment regimens expands. Treatment for extensively drug-resistant TB (XDR-TB, defined as resistance to R, any fluoroquinolone and at least one of B or L) remains much more difficult and treatment success rates are typically", "44 Global tuberculosis report 2025 A global modelling study published in 2016 estimat - ed that about a quarter of the world\u2019s population had been infected with M. tuberculosis (7). More recent anal- yses and commentary suggest that the number of those currently infected is lower, given that some people will clear the infection (8, 9) . Following infection, the risk of developing TB disease is highest in the first 2 years (approximately 5%), after which it is much lower (10). The probability of developing TB disease is much higher among people living with HIV, and among people affect- ed by risk factors such as undernutrition, diabetes, smoking and alcohol consumption. TB preventive treatment (TPT) is available to treat TB infection in people at risk of developing TB. Recom - mended options include: a weekly dose of H and P for 3 months (3HP), a daily dose of H and R for 3 months (3HR), a daily dose of H and P for 1 month (1HP), a dai - ly dose of R for 4 months (4R) and a daily dose of H for 6 months (6H) or 9 months (9H) (11). In people exposed to MDR/RR-TB, a daily dose of Lfx for 6 months (6Lfx) is recommended. The only licensed vaccine for prevention of TB dis - ease is the bacille Calmette-Gu\u00e9rin (BCG) vaccine. The BCG vaccine was introduced over 100 years ago, pre - vents severe forms of TB in children and is widely used. There is currently no licenced vaccine that is effective in preventing TB disease in adults, either before or after exposure to TB infection; however, results from a Phase II trial of the M72/AS01E candidate are promising (12). This vaccine is now in a Phase III trial, along with five other vaccine candidates. References 1. Hershkovitz I, Donoghue HD, Minnikin DE, May H, Lee OY, Feldman M, et al. Tuberculosis origin: the Neolithic scenario. Tuberculosis. 2015;95 Suppl 1:S122\u20136 (https://doi.org/10.1016/j.tube.2015.02.021). 2. Sakula A. Robert Koch: centenary of the discovery of the tubercle bacillus, 1882. Thorax. 1982;37(4):246\u201351 (https://doi.org/10.1136/thx.37.4.246). 3. WHO consolidated guidelines on tuberculosis. Module 3: Diagnosis. Geneva: World Health Organization; 2025 (https://iris.who.int/handle/10665/381003). Licence: CC BY-NC-SA 3.0 IGO. 4. WHO consolidated guidelines on tuberculosis. Module 2: Screening - systematic screening for tuberculosis disease. Geneva: World Health Organization, 2021 ( https://iris.who.int/handle/10665/340255 ). Licence: CC BY-NC-SA 3.0 IGO. 5. Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams", "BG, Nagelkerke NJ. Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One. 2011;6(4):e17601 (https://doi.org/10.1371/journal.pone.0017601). 6. WHO consolidated guidelines on tuberculosis. Module 4: treatment and care. Geneva: World Health Organization; 2025 (https://iris.who.int/handle/10665/380799 ). Licence: CC BY-NC-SA 3.0 IGO. 7. Houben RMGJ, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PloS Med. 2016 (https://doi.org/10.1371/journal.pmed.1002152 ). 8. Emery JC, Richards AS, Dale KD, McQuaid FC, White RG, Denholm JT and Houben RMGJ. Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease. Proc Biol Sci. 2021 (https://royalsocietypublishing.org/doi/full/10.1098/rspb.2020.1635 ). 9. Behr MA, Edelstein PH, Ramakrishnan L. Is Mycobacterium tuberculosis infection life long? BMJ 2019;367:l5770 ( https:// www.bmj.com/content/367/bmj.l5770 ). 10. Menzies NA, Wolf E, Connors D, Bellerose M, Sbarra AN, Cohen T et al. Progression from latent infection to active disease in dynamic tuberculosis transmission models: a systematic review of the validity of modelling assumptions. Lancet Infect Dis. 2018;18(8):e228\u2013e38 ( https://doi.org/10.1016/S1473-3099(18)30134-8 ). 11. WHO consolidated guidelines on tuberculosis. Module 1: Prevention \u2013 tuberculosis preventive treatment, second edition. Geneva: World Health Organization; 2024 ( https://iris.who.int/handle/10665/378536 ). Licence: CC BY-NC-SA 3.0 IGO. 12. Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B et al. Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis. N Eng J Med. 2019;381(25):2429\u201339 (https://doi.org/10.1056/nejmoa1909953).", "45 45 ANNEX 2 Data sources and access ly enrolled in HIV care, detection of TB among people newly enrolled in HIV care, and provision of antiretrovi - ral therapy for TB patients living with HIV were collected by the Joint United Nations Programme on HIV/AIDS (UNAIDS). These data were jointly validated by WHO and UNAIDS, and then uploaded into the WHO global TB database. Following review and follow-up with countries, the data used for the main part of this report were those that were available on 30 July 2025 . Table A2.1 shows the number of countries and areas that had reported data by 30 July 2025. Indicators in the Sustainable Development Goals (SDGs) associated with TB incidence were imported into the global TB database on 7 July 2025. Table A2.2 shows the data sources used. Population estimates from the United Nations Pop - ulation Division\u2019s 2024 revision of World Population Prospects 3 were imported into the global TB database on 2 July 2024 and used in the analyses for this report. A2.2 Accessing TB data using the WHO website Most of the data held in the WHO global TB database can be accessed via the WHO TB data web page. 4 This page provides comma-separated value (CSV) data files and data visualizations, as well as country, regional and global profiles. 3 https://population.un.org/wpp/ 4 https://www.who.int/teams/global-tuberculosis-programme/ data A2.1 Database contents The Global tuberculosis report 2025 is based on data requested annually from 215 countries and areas, including all 194 World Health Organization (WHO) Member States. Data are stored in the global TB data - base, which is managed by the TB Monitoring, Evaluation and Strategic Information unit of WHO\u2019s Department for HIV, Tuberculosis, Hepatitis and Sexually Transmitted Infections. The department has implemented annual rounds of data collection since 1995. The main round of data col - lection for this report took place in April and May 2025. As in previous years, data were collected on the follow - ing: TB case notifications and treatment outcomes, including breakdowns by TB case type, age, sex, HIV sta- tus and drug resistance; laboratory diagnostic services; monitoring and evaluation, including surveillance and surveys specifically related to drug-resistant TB; contact screening and TB preventive treatment; digital systems for TB surveillance; TB infection control; engagement of all public and private care providers in TB prevention and care; community engagement; specific elements of the WHO multisectoral accountability", "framework for TB; budgets of national TB programmes (NTPs); use of general health services (hospitalization and outpa - tient visits) during treatment; and NTP expenditures. A shortened version of the questionnaire was used for high-income countries as defined by the World Bank 1 or low-incidence countries, defined as countries with an incidence rate of <20 cases per 100 000 population or <10 cases in total in 2023. High TB burden countries and selected other regional priority countries were also asked to continue reporting monthly or quarterly provisional notification data. This process started in 2020 to monitor trends in the context of the COVID-19 pandemic. Countries and areas reported data via a dedicated website.2 Countries in the European Union submitted data on notifications and treatment outcomes to the TESSy system managed by the European Centre for Dis - ease Prevention and Control (ECDC). Data from TESSy were uploaded into the WHO global TB database. Additional data about the provision and completion of TB preventive treatment to people newly or current - 1 https://datahelpdesk.worldbank.org/knowledgebase/ articles/906519-world-bank-country-and-lending-groups 2 https://extranet.who.int/tme TABLE A2.1 Reporting of data in the 2025 round of global TB data collection COUNTRIES AND AREAS WHO MEMBER STATES NUMBER NUMBER THAT REPORTED DATA NUMBER NUMBER THAT REPORTED DATA African Region 47 46 47 46 Region of the Americas 45 35 35 29 South-East Asia Region 10 10 10 10 European Region 54 40 53 39 Eastern Mediterranean Region 22 21 21 20 Western Pacific Region 37 32 28 26 Global 215 184 194 170", "46 Global tuberculosis report 2025 Data reported by countries, such as time series for case notifications and treatment outcomes, and WHO\u2019s estimates of TB disease burden, can be downloaded as CSV files covering all years for which data are available. They can be imported into many applications such as spreadsheets, databases and statistical analysis soft - ware. These files are the primary resource for anyone interested in conducting their own analyses of the records in the global TB database. A data dictionary that defines each of the variables available in the CSV files is also available. The CSV files are generated on demand directly from the WHO global TB database, and may therefore include updates received after publication of the Global tubercu- losis report 2025. A2.3 Accessing TB data using the WHO Global Health Observatory The WHO Global Health Observatory (GHO) 1 is a portal that provides access to data and analyses for monitoring the global health situation; it includes a data repository. Data from WHO\u2019s global TB database can be viewed, filtered, aggregated and downloaded from within the GHO data repository.2 There is also an application programme interface (API)3 using the open data protocol. The API allows ana - lysts and programmers to use GHO data directly in their software applications. 1 https://www.who.int/data/gho 2 https://www.who.int/data/gho/data/themes/tuberculosis 3 https://www.who.int/data/gho/info/gho-odata-api SDG INDICATOR DISPLAY NAME IN PROFILE DATA SOURCE NAME AT SOURCE SOURCE URL 1.1.1 Population living below the international poverty line (% of population) UN SDG database Proportion of population below the international poverty line of US$1.90 per day https://unstats.un.org/SDGAPI/v1/sdg/Series/ Data?seriesCode=SI_POV_DAY1 1.3.1 Population covered by social protection floors/systems (% of population) World Bank Coverage of social protection and labor programs (% of population) http://data.worldbank.org/indicator/per_allsp. cov_pop_tot 2.1.1 (alternative) Prevalence of under nutrition (% of population aged \u226518 years) WHO-GHO Prevalence of underweight among adults, BMI <18.5 (crude estimate) (%) https://ghoapi.azureedge.net/api/NCD_ BMI_18C 3.3.1 (alternative) HIV prevalence (% of population aged 15\u201349 years) WHO-GHO Prevalence of HIV among adults aged 15 to 49 (%) https://ghoapi.azureedge.net/api/ MDG_0000000029 3.4.1 (alternative) Diabetes prevalence (% of population aged \u226518 years) WHO-GHO Prevalence of diabetes, age- standardized https://ghoapi.azureedge.net/api/NCD_ DIABETES_PREVALENCE_AGESTD 3.5.2 (alternative) Alcohol use disorders, 12 month prevalence (% of population aged \u226515 years) WHO-GHO Alcohol use disorders (15+), 12 month prevalence (%) with 95% https://ghoapi.azureedge.net/api/ SA_0000001462 3.a.1 (alternative) Smoking prevalence (% of population aged \u226515 years) WHO-GHO Estimate of current tobacco smoking prevalence (%) (age-standardized rate) https://ghoapi.azureedge.net/api/M_Est_smk_ curr_std 3.8.1 UHC", "index of essential service coverage (based on 14 tracer indicators including TB treatment) WHO-GHO UHC index of essential service coverage https://ghoapi.azureedge.net/api/UHC_INDEX_ REPORTED 3.8.2 Greater than 10% of total household expenditure or income on health (% of population) WHO-GHO Catastrophic out-of-pocket health spending (SDG indicator 3.8.2) https://ghoapi.azureedge.net/api/ FINPROTECTION_CATA_TOT_10_POP 3.8.2 (alternative) Health expenditure per capita, PPP (current international $) World Bank Current health expenditure per capita, PPP (current international $) http://data.worldbank.org/indicator/SH.XPD. CHEX.PP .CD 7.1.2 Access to clean fuels and technologies for cooking (% of population) World Bank Access to clean fuels and technologies for cooking (% of population) http://data.worldbank.org/indicator/EG.CFT. ACCS.ZS 8.1.1 (alternative) GDP per capita, PPP (constant 2011 international $) World Bank GDP per capita, PPP (constant 2011 international $) http://data.worldbank.org/indicator/NY.GDP . P C A P. P P. K D 10.1.1 (alternative) GINI index (0=perfect equality, 100=perfect inequality) World Bank GINI index (World Bank estimate) http://data.worldbank.org/indicator/SI.POV. GINI 11.1.1 Population living in slums (% of urban population) UN SDG database Proportion of urban population living in slums (%) https://unstats.un.org/SDGAPI/v1/sdg/Series/ Data?seriesCode=EN_LND_SLUM TABLE A2.2 Data sources for indicators in the SDGs that are associated with TB incidence", "47 47 ANNEX 3 WHO global lists of high TB burden countries A3.1 Background During the period 1998 to 2015, the concept of a \u201chigh burden country\u201d (HBC) became familiar and widely used in the context of tuberculosis (TB). The first global list developed by the World Health Organization (WHO) consisted of 22 HBCs with approximately 80% of the world\u2019s TB cases; this was established in 1998. Subsequently two other HBC lists, for HIV-associated TB and multidrug-resistant TB (MDR-TB), were defined. In 2015, three WHO global lists of HBCs \u2013 for TB, TB/ HIV and MDR-TB \u2013 were in use. With a new era of the United Nations (UN) Sustainable Development Goals (SDGs) and the WHO End TB Strategy starting in 2016, a thorough review of the three lists was undertaken by the WHO Global Tuberculosis Programme in 2015 (1). This included consideration of whether the lists should be modified (and if so how) or whether they should be dis - continued. The outcome of the review was the definition of three new global HBC lists, of 30 countries each, for the period 2016\u20132020: one for TB, one for TB/HIV and one for MDR-TB. WHO conducted a consultation process in 2020 and early 2021, as the basis for defining updated global HBC lists for 2021\u20132025. A3.2 Global HBC lists being used by WHO, 2021\u20132025 Three global HBC lists for 2021\u20132025 were established: one for TB, one for HIV-associated TB and one for MDR/ rifampicin-resistant TB (MDR/RR-TB). The lists were defined using the same criteria as those agreed for the 2016\u20132020 lists, in combination with the WHO estimates (for 2019) of the incidence of TB, HIV-associated TB and rifampicin-resistant TB that were published in WHO\u2019s Global Tuberculosis Report 2020 . Full details are availa - ble in a background document (2). The criteria for all three lists are the same: \u25b6 the top 20 countries in terms of their estimated abso- lute number of new (incident) cases in 2019; plus \u25b6 the 10 countries with the most severe burden in terms of the incidence rate (new cases per 100 000 popula - FIG. A3.1 The three global lists of high-burden countries for TB, HIV-associated TB and MDR/RR-TB being used by WHO in the period 2021\u20132025, and their areas of overlap Azerbaijan Belarus Kazakhstan Nepal Peru Republic of Moldova Russian Federation Somalia Tajikistan Ukraine Uzbekistan Zimbabwe Brazil Central African Republic Congo Ethiopia", "Gabon Kenya Lesotho Liberia Namibia Thailand Uganda United Republic of Tanzania China Democratic Republic of the Congo India Indonesia Mozambique Myanmar Nigeria Philippines South Africa Zambia Angola Bangladesh Democratic People\u2019s Republic of Korea Mongolia Pakistan Papua New Guinea Viet Nam Botswana Cameroon Eswatini Guinea Guinea-Bissau Malawi Russian Federation Zimbabwe Sierra Leone TB/HIV MDR/RR-TB TB", "48 Global tuberculosis report 2025 tion in 2019) that are not already in the top 20, and that meet a minimum threshold in terms of their absolute number of cases. The thresholds are 10 000 new cases per year for TB; and 1000 new cases per year for HIV-associated TB and rifampicin-resistant TB. The 30 countries that are in each of the three lists are shown in Fig. A3.1 and Table A3.1 . There is overlap among the three lists, but 49 countries are in at least one of them. Each list accounted for 86\u201390% of the estimated global incidence in 2019. The main changes compared with the previous lists for 2016\u20132020 were: \u25b6 The 30 high TB burden countries. Cambodia, the Russian Federation and Zimbabwe tran - sitioned out of the list; Gabon, Mongolia and Uganda joined the list. \u25b6 The 30 high TB/HIV burden countries. Angola, Chad, Ghana and Papua New Guinea transitioned out of the list; Gabon, Guinea, the Philippines and the Russian Federation joined the list. \u25b6 The 30 high MDR/RR-TB burden countries. Ethi- opia, Kenya and Thailand transitioned out of the list; Mongolia, Nepal and Zambia joined the list. The lists provide a focus for global action on TB, HIV-associated TB and drug-resistant TB in the countries where progress is most needed to achieve the targets set in WHO\u2019s End TB Strategy, the UN SDGs and political declarations at UN high-level meetings on TB ( Box 1, Table 1). They also help to build and sustain national political commitment and funding in the countries with the highest bur - den in terms of absolute numbers or severity and promote global monitoring of progress in a well- defined set of countries. The 30 high TB burden countries are given par - ticular attention in the report. Where estimates of disease burden and assessment of progress in the response are for HIV-associated TB or MDR/RR-TB specifically, the countries in the other two lists are given particular attention. Country profiles for all countries are available online, including in the report mobile app. A3.3 Global TB watchlist Alongside the three updated global HBC lists, WHO established a \u201cglobal TB watchlist\u201d. This consists of the three countries that exited the global list of 30 high TB burden countries in 2021, but which nonetheless warrant continued attention and will remain a priority in terms of support from WHO. The three countries", "in the watchlist are Cambodia, the Russian Federation and Zimbabwe. TABLE A3.1 Countries in the three global lists of high-burden countries for TB, HIV-associated TB and MDR/RR- TB being used by WHO in the period 2021\u20132025. The red square indicates that a country is in a list. COUNTRY TB TB/HIV MDR/RR-TB Angola \uf0a2 \uf0a2 Azerbaijan \uf0a2 Bangladesh \uf0a2 \uf0a2 Belarus \uf0a2 Botswana \uf0a2 Brazil \uf0a2 \uf0a2 Cameroon \uf0a2 Central African Republic \uf0a2 \uf0a2 China \uf0a2 \uf0a2 \uf0a2 Congo \uf0a2 \uf0a2 Democratic People\u2019s Republic of Korea \uf0a2 \uf0a2 Democratic Republic of the Congo \uf0a2 \uf0a2 \uf0a2 Eswatini \uf0a2 Ethiopia \uf0a2 \uf0a2 Gabon \uf0a2 \uf0a2 Guinea \uf0a2 Guinea-Bissau \uf0a2 India \uf0a2 \uf0a2 \uf0a2 Indonesia \uf0a2 \uf0a2 \uf0a2 Kazakhstan \uf0a2 Kenya \uf0a2 \uf0a2 Kyrgyzstan \uf0a2 Lesotho \uf0a2 \uf0a2 Liberia \uf0a2 \uf0a2 Malawi \uf0a2 Mongolia \uf0a2 \uf0a2 Mozambique \uf0a2 \uf0a2 \uf0a2 Myanmar \uf0a2 \uf0a2 \uf0a2 Namibia \uf0a2 \uf0a2 Nepal \uf0a2 Nigeria \uf0a2 \uf0a2 \uf0a2 Pakistan \uf0a2 \uf0a2 Papua New Guinea \uf0a2 \uf0a2 Peru \uf0a2 Philippines \uf0a2 \uf0a2 \uf0a2 Republic of Moldova \uf0a2 Russian Federation \uf0a2 \uf0a2 Sierra Leone \uf0a2 Somalia \uf0a2 South Africa \uf0a2 \uf0a2 \uf0a2 Tajikistan \uf0a2 Thailand \uf0a2 \uf0a2 Uganda \uf0a2 \uf0a2 Ukraine \uf0a2 United Republic of Tanzania \uf0a2 \uf0a2 Uzbekistan \uf0a2 Viet Nam \uf0a2 \uf0a2 Zambia \uf0a2 \uf0a2 \uf0a2 Zimbabwe \uf0a2 \uf0a2", "49 A3.4 Global HBC lists for 2026\u20132030 WHO will update the current lists for the 5-year period 2026\u20132030 towards the end of 2025. The lists will be defined according to the same criteria as those already used for the 2016\u20132020 and 2021\u20132025 lists. Incidence estimates for 2024 will provide the basis for the updated lists. Annex 3. WHO global lists of high TB burden countries A3.5 Categorization of all countries and areas according to their level of TB disease burden A categorization of all countries and areas according to their estimated TB incidence rate in 2024 is provided in Table A3.2 . Countries that have moved categories between 2015 and 2024 are listed in Table A3.3. References 1. World Health Organization. Use of high burden country lists for TB by WHO in the post-2015 era (discussion paper). Geneva: World Health Organization; 2015 ( https://www.who.int/publications/m/item/who-htm-tb-2015-29 ). 2. World Health Organization. WHO global lists of high burden countries for tuberculosis (TB), TB/HIV and multidrug/ rifampicin-resistant TB (MDR/RR-TB), 2021\u20132025: background document. Geneva. World Health Organization; 2021 (https://apps.who.int/iris/handle/10665/341980 ).", "50 Global tuberculosis report 2025 TABLE A3.2 Categorization of all countries and areas according to their level of TB disease burden in 2024 Countries are categorized using the estimated TB incidence rate (new cases per 100 000 population) in 2024. The categories were defined alongside the establishment of the WHO global HBC lists for 2021\u20132025 (2). Category 1, severely endemic; Category 2, highly endemic; Category 3, endemic; Category 4, upper moderate; Category 5, lower moderate; Category 6, low. INCIDENCE CATEGORY COUNTRIES AND AREAS INCLUDED, BY WHO REGION a NUMBER OF COUNTRIES AND AREAS, AND CATEGORY SHARE (%) OF THE TOTAL ESTIMATED NUMBER OF INCIDENT TB CASES GLOBALLY IN 2024 Category 1 (\u2265500 incident cases per 100 000 population in 2024) African Region : Lesotho Western Pacific Region : Kiribati, Papua New Guinea, the Philippines 4 countries and areas 8.8% of global incident TB cases Category 2 (300\u2013499 incident cases per 100 000 population in 2024) African Region : Angola, the Central African Republic, the Congo, the Democratic Republic of the Congo, Eswatini, Gabon, Mozambique, Namibia, Sierra Leone, South Africa, South Sudan Eastern Mediterranean Region : Djibouti South-East Asia Region : Myanmar, Timor-Leste Western Pacific Region : Indonesia, the Marshall Islands, Mongolia 17 countries and areas 23% of global incident TB cases Category 3 (100\u2013299 incident cases per 100 000 population in 2024) African Region : Botswana, Cameroon, Chad, Equatorial Guinea, Eritrea, Ethiopia, the Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Madagascar, Malawi, Nigeria, Senegal, Uganda, the United Republic of Tanzania, Zambia, Zimbabwe Region of the Americas : Bolivia (Plurinational State of), El Salvador, Haiti, Peru Eastern Mediterranean Region : Afghanistan, Pakistan, Somalia European Region : Greenland, Kyrgyzstan South-East Asia Region : Bangladesh, Bhutan, India, Nepal, Thailand Western Pacific Region : Cambodia, Fiji, the Lao People\u2019s Democratic Republic, Micronesia (Federated States of), Nauru, the Solomon Islands, Tuvalu, Viet Nam 42 countries and areas 54% of global incident TB cases Category 4 (50\u201399 incident cases per 100 000 population in 2024) African Region : Algeria, Burkina Faso, Burundi, C\u00f4te d\u2019Ivoire, Mali, Mauritania, the Niger, Rwanda, S\u00e3o Tom\u00e9 and Principe Region of the Americas : the Dominican Republic, Ecuador, Guyana, Panama, Paraguay Eastern Mediterranean Region : Libya, Morocco European Region : Azerbaijan, Republic of Moldova, Romania, Tajikistan, Ukraine, Uzbekistan South-East Asia Region : Sri Lanka Western Pacific Region : Brunei Darussalam, China, Hong Kong SAR, China, Macao SAR, Guam, Malaysia, Niue 29 countries and", "areas 3.1% of global incident TB cases Category 5 (10\u201349 incident cases per 100 000 population in 2024) African Region : Benin, Cabo Verde, the Comoros, Mauritius, the Seychelles, Togo Region of the Americas : Argentina, the Bahamas, Belize, Brazil, Chile, Colombia, Cuba, Guatemala, Honduras, Mexico, Nicaragua, Suriname, Trinidad and Tobago, Uruguay, Venezuela (Bolivarian Republic of) Eastern Mediterranean Region : Bahrain, Egypt, Iran (Islamic Republic of), Iraq, Kuwait, Lebanon, Oman, Qatar, the Sudan, the Syrian Arab Republic, Tunisia, Yemen European Region : Albania, Armenia, Belarus, Bosnia and Herzegovina, Bulgaria, Georgia, Kazakhstan, Latvia, Lithuania, Malta, Montenegro, North Macedonia, Poland, Portugal, the Russian Federation, Turkmenistan, T\u00fcrkiye South-East Asia Region : Maldives Western Pacific Region : China, French Polynesia, New Caledonia, the Northern Mariana Islands, Palau, the Republic of Korea, Singapore, Tokelau, Vanuatu 60 countries and areas 10% of global incident TB cases Category 6 (<10 incident cases per 100 000 population in 2024) Region of the Americas : Anguilla, Antigua and Barbuda, Aruba, Barbados, Bermuda, the British Virgin Islands, Canada, the Cayman Islands, Costa Rica, Cura\u00e7ao, Dominica, Grenada, Jamaica, Montserrat, Puerto Rico, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Sint Maarten (Dutch part), the Turks and Caicos Islands, the United States of America Eastern Mediterranean Region : Jordan, the occupied Palestinian territory, including east Jerusalem, Saudi Arabia, the United Arab Emirates European Region : Andorra, Austria, Belgium, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Luxembourg, Monaco, Netherlands (Kingdom of the), Norway, San Marino, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom of Great Britain and Northern Ireland Western Pacific Region : American Samoa, Australia, the Cook Islands, Japan, New Zealand, Samoa, Tonga, Wallis and Futuna 62 countries and areas 0.58% of global incident TB cases SAR, Special Administrative Region. a The Democratic Republic of Korea is not listed in the table because estimates of TB incidence are currently under review.", "51 TABLE A3.3 Countries that changed incidence category (n=61) between 2015 and 2024, by WHO region The colour coding indicates whether countries moved to a lower category ( green) or a higher category ( orange). Darker green or orange indicates countries that moved down or up, respectively, by more than one category. An asterisk indicates countries that are in WHO\u2019s list of 30 high TB burden countries, 2021\u20132025. a) African Region (n=16) COUNTRIES AND AREAS INCIDENCE CATEGORY IN 2015 INCIDENCE CATEGORY IN 2024 Central African Republic* Severely endemic Highly endemic Eswatini Severely endemic Highly endemic Namibia* Severely endemic Highly endemic South Africa* Severely endemic Highly endemic Botswana Highly endemic Endemic Kenya* Highly endemic Endemic United Republic of Tanzania* Highly endemic Endemic Zambia* Highly endemic Endemic Burundi Endemic Upper moderate C\u00f4te d\u2019Ivoire Endemic Upper moderate Mauritania Endemic Upper moderate S\u00e3o Tom\u00e9 and Pr\u00edncipe Endemic Upper moderate Benin Upper moderate Lower moderate Cabo Verde Upper moderate Lower moderate Togo Upper moderate Lower moderate Seychelles Low Lower moderate b) Region of the Americas (n=8) COUNTRIES AND AREAS INCIDENCE CATEGORY IN 2015 INCIDENCE CATEGORY IN 2024 Haiti Highly endemic Endemic Guyana Endemic Upper moderate El Salvador Upper moderate Endemic Nicaragua Upper moderate Lower moderate Cayman Islands Lower moderate Low Costa Rica Lower moderate Low Ecuador Lower moderate Upper moderate Cuba Low Lower moderate c) Eastern Mediterranean Region (n=5) COUNTRIES AND AREAS INCIDENCE CATEGORY IN 2015 INCIDENCE CATEGORY IN 2024 Djibouti Severely endemic Highly endemic Sudan Upper moderate Lower moderate Tunisia Upper moderate Lower moderate Libya Lower moderate Upper moderate Saudi Arabia Lower moderate Low Annex 3. WHO global lists of high TB burden countries", "52 Global tuberculosis report 2025 d) European Region (n=18) COUNTRIES AND AREAS INCIDENCE CATEGORY IN 2015 INCIDENCE CATEGORY IN 2024 Georgia Endemic Lower moderate Republic of Moldova Endemic Upper moderate Tajikistan Endemic Upper moderate Ukraine Endemic Upper moderate Armenia Upper moderate Lower moderate Belarus Upper moderate Lower moderate Kazakhstan Upper moderate Lower moderate Latvia Upper moderate Lower moderate Lithuania Upper moderate Lower moderate Russian Federation Upper moderate Lower moderate Turkmenistan Upper moderate Lower moderate Croatia Lower moderate Low Estonia Lower moderate Low Hungary Lower moderate Low Serbia Lower moderate Low Spain Lower moderate Low United Kingdom of Great Britain and Northern Ireland Lower moderate Low Malta Low Lower moderate e) South-East Asia Region (n=1) COUNTRIES AND AREAS INCIDENCE CATEGORY IN 2015 INCIDENCE CATEGORY IN 2024 Maldives Upper moderate Lower moderate f) Western Pacific Region (n=13) COUNTRIES AND AREAS INCIDENCE CATEGORY IN 2015 INCIDENCE CATEGORY IN 2024 Cambodia Highly endemic Endemic Malaysia Endemic Upper moderate Tokelau Endemic Lower moderate China* Upper moderate Lower moderate Fiji Upper moderate Endemic Nauru Upper moderate Endemic Northern Mariana Islands Upper moderate Lower moderate Palau Upper moderate Lower moderate Republic of Korea Upper moderate Lower moderate Vanuatu Upper moderate Lower moderate Japan Lower moderate Low Tonga Lower moderate Low Niue Low Upper moderate", "53 ANNEX 4 Updates to estimates of TB disease burden The report includes estimates of tuberculosis (TB) inci - dence and mortality for the period 2010\u20132024, estimates of TB incidence and mortality disaggregated by age and sex for 2024, and estimates of the incidence of rifampic- in-resistant TB (RR-TB) for the period 2015\u20132024. Updates to the methods used to produce these esti - mates are summarized below. A4.1 General updates, methods to estimate TB incidence In September 2024, the World Health Organization (WHO) convened its Global Task Force on TB Impact Measurement (1). The main purpose of the meeting was to conduct a comprehensive review of methods used by WHO to produce estimates of TB incidence and mor - tality. Two new methods for producing estimates of TB incidence \u2013 both of which leverage the universal health coverage (UHC) Service Coverage Index (SCI) (2) \u2013 were agreed upon (3, 4). In this report, the two new methods were used as follows: \u25b6 Upward adjustment of TB case notifications based on country-specific UHC SCI values. This method was used for 98 countries, which collectively accounted for 3.8% of the global number of incident TB cases in 2024. For these countries, this type of upward adjust- ment has replaced the previous method of a standard upward adjustment of TB notifications. \u25b6 Upward adjustment of TB case notifications accord - ing to an incidence-to-notification ratio derived from a UHC SCI\u2013based statistical model. This method was used for 32 countries, which collectively accounted for 7.4% of the global number of incident cases in 2024. For these countries, this type of upward adjust- ment has replaced the previous method of using case notifications combined with expert opinion about case detection gaps. There were six countries for which the new UHC SCI\u2013 based method was not a suitable replacement for the previous method of using case notifications combined with expert opinion about case detection gaps. A cus - tomized approach was used instead, based on in-depth bilateral discussions with national TB programmes (NTPs) about the latest available data and recent devel - opments in TB services as well as health services more broadly. Finally, for 32 countries with a very low burden of TB (<10 reported cases per year), incidence estimates in this report are based on TB case notifications, with no adjustment. This approach has replaced the previous method of using case notifications combined with", "a standard upward adjustment. All other methods used to estimate TB incidence remain unchanged from those used for the Global tuber- culosis report 2024 (5). A4.2 Country-specific updates Brazil For the period 2010\u20132019, TB incidence was estimated through upward adjustment of TB case notifications according to the estimated proportion of incident cases that were treated for TB. This proportion was estimated using TB-related mortality data (6). Cambodia A third national TB prevalence survey was completed in Cambodia in July 2024. The results were used alongside findings from previous surveys (implemented in 2002 and 2011) to update TB incidence and mortality esti - mates for the period 2010\u20132024. India Updated cause-of-death data from the Sample Regis - tration System (SRS) for 2 years (2020 and 2022) were incorporated into the country-specific dynamic model that is used to produce TB incidence and mortality esti - mates, following their official publication in 2025 (7). Estimates of the incidence of RR-TB for 2015\u20132024 were produced using two major data sources: results from a national survey of anti-TB drug resistance in 2016 and routine surveillance data for 2024. Previously (until the Global tuberculosis report 2024 ), only the national survey data were available for use. The 2024 surveillance data met the coverage and quality criteria used by WHO to determine whether routine surveillance data can be used to estimate the incidence of RR-TB, and were reported to WHO following extensive data validation by the country\u2019s National TB Elimination Programme. Myanmar TB case notification data for 2024 indicated that dis - ruptions to TB diagnosis and treatment during the coronavirus disease (COVID-19) pandemic were less", "54 Global tuberculosis report 2025 severe than previously estimated. Estimates of TB incidence and mortality since 2020 were revised accord- ingly. Thailand Data about the numbers of people screened for TB since the COVID-19 pandemic indicated that TB servic - es recovered to pre-pandemic levels more rapidly than previously suggested by TB case notification data alone. Estimates of TB incidence and mortality were revised accordingly. A4.3 General updates Several countries reported historical data that were previously missing or made corrections to previous - ly reported data, but these had limited or negligible impact on updated estimates. In July 2025, the Joint United Nations Programme on HIV/AIDS (UNAIDS) published updated estimates of HIV prevalence and mortality (8). These were used in replacement of previous estimates. A4.4 Overview of data sources for the 30 high TB burden and three global TB watchlist countries The main data sources currently available to inform estimates of TB disease burden in the 30 high TB bur - den countries and three global TB watchlist countries (Annex 3 ) are summarized in Table A4.1 . Details about the methods used for all countries are provided in the report webpages (Section 1.1 and Sec - tion 1.2) and the technical appendix . References 1. WHO Global Task Force on TB Impact Measurement [website]. World Health Organization; 2025 ( https://www.who.int/ groups/global-task-force-on-tb-impact-measurement ). 2. World Health Organization/World Bank. Tracking universal health coverage: 2023 global monitoring report. Geneva: World Health Organization; 2023 (https://iris.who.int/handle/10665/374059). Licence: CC BY-NC-SA 3.0 IGO. 3. TB incidence estimates for the Sustainable Development Goal and End TB Strategy 2025 milestone and 2030 targets assessment: data sources, analytical methods and process. Background document 3 for meeting of WHO Global Task Force on TB Impact Measurement, 25\u201327 September 2024. Geneva: World Health Organization; 2024 (https://cdn.who.int/media/docs/default-source/hq-tuberculosis/global-task-force-on-tb-impact-measurement/ meetings/2024-09/background-documents/background1-tbincidenceestimates.pdf?sfvrsn=ee240ead_11 ). 4. WHO Global Task Force on TB Impact Measurement: Report of a meeting on methods for producing estimates of TB incidence and mortality required for the End TB Strategy and Sustainable Development Goal 2025 milestones and 2030 targets assessment, 25\u201327 September 2024. Geneva: World Health Organization; 2024 (https://cdn.who.int/media/docs/default-source/hq-tuberculosis/global-task-force-on-tb-impact-measurement/ meetings/2024-09/meeting-documents/taskforcemeeting_september2024_report.pdf?sfvrsn=d50f0939_3 ). 5. Global tuberculosis report 2024. Geneva: World Health Organization; 2024 ( https://iris.who.int/handle/10665/379339 ). Licence: CC BY-NC-SA 3.0 IGO. 6. Chitwood MH, Pelissari DM, Drummond Marques da Silva G, Bartholomay P , Rocha MS, Sanchez M et al. Bayesian evidence synthesis to estimate subnational TB incidence: an application in Brazil. Epidemics. 2021;35:100443 (https://doi.org/10.1016/j.epidem.2021.100443 ).", "7. Sample Registration System (SRS) \u2013 cause of death in India 2020\u20132022. New Delhi: Office of the Registrar-General and Census Commissioner of India; 2023 (https://censusindia.gov.in/nada/index.php/catalog/45568). 8. AIDS, crisis and the power to transform: UNAIDS Global AIDS update. Geneva: Joint United Nations Programme on HIV/ AIDS; 2025 (https://www.unaids.org/en/resources/documents/2025/2025-global-aids-update ). Licence: CC BY-NC-SA 3.0 IGO.", "55Annex 4. Updates to estimates of TB disease burden TABLE A4.1 Sources of data available to inform estimates of TB disease burden in the 30 high TB burden countries and the three global TB watchlist countries, 2010\u20132024 a Blue indicates that a source is available, orange indicates it will be available in the near future, and red indicates that a source is not available. COUNTRY NOTIFICATION DATA STANDARDS AND BENCHMARK ASSESSMENT b NATIONAL INVENTORY STUDYc NATIONAL TB PREVALENCE SURVEY d NATIONAL DRUG RESISTANCE SURVEY OR SURVEILLANCE e NATIONAL VR DATA OR MORTALITY SURVEY f Angola 2000\u20132024 2019, 2023 \u2013 \u2013 2022\u20132024 \u2013 Bangladesh 2000\u20132024 2019, 2022 \u2013 2015 2011, 2019, 2024 \u2013 Brazil 2000\u20132024 2018 \u2013 NA 2008 2000\u20132023 Cambodia 2000\u20132024 2018, 2022 \u2013 2002, 2011, 2023 2007, 2018, 2024 See footnote g Central African Republic 2000\u20132024 2019, 2022 \u2013 \u2013 2009, 2024 \u2013 China 2000\u20132024 \u2013 2018, 2022 2000, 2010 2007, 2013, 2020, 2022\u2013 2024 2004\u20132021 Congo 2000\u20132024 2019, 2022 \u2013 \u2013 2024 Democratic People\u2019s Republic of Korea 2000\u20132024 2017 \u2013 2016 2014 Democratic Republic of the Congo 2000\u20132024 2019, 2022 \u2013 \u2013 2017 \u2013 Ethiopia 2000\u20132024 2016, 2023 \u2013 2011 2005, 2018, 2018, 2020, 2023 \u2013 Gabon 2000\u20132024 2018, 2020 \u2013 \u2013 2023 \u2013 India 2000\u20132024 2019 2016 2019\u20132021 2016, 2024 2000\u20132019 , 2020, 2022 Indonesia 2000\u20132024 2019, 2022 2017, 2023 2013\u20132014 2018, 2023, 2024 2006\u20132007, 2009\u20132015 Kenya 2000\u20132024 2017, 2021 2013 2015 2014, 2024, 2020, 2024 \u2013 Lesotho 2000\u20132024 2017, 2022 \u2013 2019 2014, 2024, 2019\u20132024 \u2013 Liberia 2000\u20132024 2015, 2019 \u2013 \u2013 \u2013 \u2013 Mongolia 2000\u20132024 2015, 2018 2026 2014\u20132015 2007, 2016, 2018\u20132024 2016\u20132019 Mozambique 2000\u20132024 2013 \u2013 2017\u20132019 2007, 2021, 2021\u20132023 \u2013 Myanmar 2000\u20132024 2017, 2022 \u2013 2009, 2018 2003, 2008, 2013, 2018, 2020, 2023, 2024 \u2013 Namibia 2000\u20132024 2019, 2022 \u2013 2017\u20132018 2008, 2015, 2018, 2020\u20132024 Nigeria 2000\u20132024 2020, 2023 \u2013 2012 2010, 2022\u20132024 \u2013 Pakistan 2000\u20132024 2019, 2022 2012, 2017 2011 2013, 2019\u20132020 2006, 2007, 2010 Papua New Guinea 2000\u20132024 2017, 2023 \u2013 \u2013 2014, 2023\u20132024 \u2013 Philippines 2000\u20132024 2016, 2019 2026 2007, 2016 2004, 2012, 2019, 2021\u20132023 2000\u20132014, 2016\u20132019 Russian Federation 2000\u20132024 2017 \u2013 NA 2016\u20132024 2000\u20132024 Sierra Leone 2000\u20132024 2015, 2020 \u2013 \u2013 \u2013 \u2013 South Africa 2000\u20132024 2019, 2022 2022 2026 2017\u20132019 2002, 2014, 2021\u20132024 2000\u20132017 Thailand 2000\u20132024 2013 \u2013 2012 2001, 2006, 2012, 2018, 2023\u20132024 2000, 2002\u20132019 Uganda 2000\u20132024 2019, 2023 \u2013 2014\u20132015 2011, 2018\u20132019, 2023 \u2013 United Republic", "of Tanzania 2000\u20132024 2018, 2023 \u2013 2012 2007, 2018, 2021\u20132024 \u2013 Viet Nam 2000\u20132024 2019, 2023 2017 2007, 2017\u20132018 2006, 2012, 2018, 2020\u20132024 \u2013 Zambia 2000\u20132024 2016, 2020 \u2013 2014 2000, 2008, 2020, 2018\u20132024 \u2013 Zimbabwe 2000\u20132024 2019, 2022 \u2013 2014 2016, 2018\u20132020, 2022\u20132024 \u2013 NA, not applicable; VR, vital registration a Data for the period 2000\u20132009 can inform estimates for the period 2010\u20132024 and are shown for this reason. The three global TB watchlist countries are Cambodia, the Russian Federation and Zimbabwe. b The WHO TB surveillance checklist of standards and benchmarks is designed to assess the quality and coverage of notification data (based on 9 core standards), VR data (1 core standard) and data for drug-resistant TB, HIV co-infection and childhood TB (3 supplementary standards). The second edition of the WHO TB surveillance checklist also includes an assessment of monitoring and evaluation related to TB care (2 supplementary standards) and TB prevention (2 supplementary standards). If more than two assessments have been done, the years of the last two only are shown. c Studies are planned in Mongolia, the Philippines and South Africa in 2026\u20132027. Prioritization of TB inventory studies is recommended in countries where a large share of TB care is provided to TB patients outside the existing NTP network. d Brazil does not meet the following criteria recommended by the WHO Global Task Force on TB Impact Measurement for implementing a national prevalence survey: TB incidence \u2265150 per 100 000 population per year, no VR system and under-5 mortality rate (probability of dying by age of 5 per 1000 live births) is >10. e Data points are shown for people without a history of previous TB treatment only. Data are available from continuous surveillance (indicated by italics in blue cells) based on routine diagnostic testing in all listed countries except Brazil, the Democratic People\u2019s Republic of Korea, the Democratic Republic of the Congo, Liberia and Sierra Leone. f Years of data availability for Indonesia, Mongolia, Pakistan and South Africa were provided to WHO by IHME. g Input data used to inform covariates for estimating TB mortality in Cambodia are available here: Ma, J., Vongpradith, A., Ledesma, J.R. et al. Progress towards the 2020 milestones of the end TB strategy in Cambodia: estimates of age and sex specific TB incidence and mortality from the Global Burden of Disease Study 2019. BMC Infect Dis 22, 904 (2022). https://doi.org/10.1186/s12879-022-07891-5", "56 Global tuberculosis report 2025 ANNEX 5 The WHO TB-SDG monitoring framework In 2017, the World Health Organization (WHO) developed a framework for monitoring of indicators in the United Nations (UN) Sustainable Development Goals (SDGs) that are strongly associated with tuberculosis (TB) inci - dence. This was done as part of the preparations for the first global ministerial conference on TB (1), building on previously published work that identified clear linkages between a range of social, economic and health-related indicators and TB incidence (2\u20134). In 2024, the framework was updated, with under - nutrition replacing undernourishment as the selected indicator for SDG 2. This followed the publication of a systematic review related to the risk of TB in people with and without undernutrition (5). The TB-SDG monitoring framework comprises 14 indicators under seven SDGs (Table A5.1). For SDG 3, the framework includes seven indicators: \u2014 coverage of essential health services; \u2014 proportion of the population with large household expenditures on health as a share of total house - hold expenditure or income; \u2014 current health expenditure per capita; \u2014 HIV prevalence; \u2014 prevalence of smoking; \u2014 prevalence of diabetes; and \u2014 prevalence of alcohol use disorders. For SDGs 1, 2, 7, 8, 10 and 11, the seven indicators select- ed for monitoring are: \u2014 proportion of the population living below the international poverty line; \u2014 proportion of the population covered by social protection floors or systems; \u2014 prevalence of undernutrition; \u2014 proportion of the population with primary reli - ance on clean fuels and technology; \u2014 gross domestic product (GDP) per capita; \u2014 Gini index for income inequality; and \u2014 proportion of the urban population living in slums. Collection and reporting of data for the 14 indicators does not require any additional data collection and reporting efforts by national TB programmes (NTPs). Nor does it require data collection and reporting efforts that go beyond those to which countries have already committed in the context of the SDGs. At the global lev - el, the UN has established a monitoring system for SDG indicators, and countries are expected to report data on an annual basis via the appropriate UN agencies (includ- ing WHO). Therefore, analysis of the status of, and trends in, the 14 indicators related to TB can be based primarily on data held in the UN\u2019s SDG database. In some cases, the official SDG indicator was not considered the", "best metric, and a better (but closely related) alternative was identified and justified (one under SDG 2, five under SDG 3, one under SDG 8 and one under SDG 10). In such cases, the data sources are one of the following: WHO, the Organisation for Economic Co-operation and Development (OECD), the Joint Unit - ed Nations Programme on HIV/AIDS (UNAIDS) or the World Bank. References 1. Monitoring and evaluation of TB in the context of the Sustainable Development Goals in Policy Briefs: WHO Global Ministerial Conference Ending TB in the Sustainable Development Era: Multisectoral Response. Geneva: World Health Organization; 2017. (https://www.who.int/publications/m/item/moscow-conference---policy-brief ). 2. Lienhardt C, Glaziou P , Uplekar M, L\u00f6nnroth K, Getahun H, Raviglione M. Global tuberculosis control: lessons learnt and future prospects. Nat Rev Microbiol. 2012;10(6):407 ( https://doi.org/10.1038/nrmicro2797). 3. L\u00f6nnroth K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P et al. Tuberculosis control and elimination 2010\u201350: cure, care, and social development. Lancet. 2010;375(9728):1814\u201329 ( https://doi.org/10.1016/S0140-6736(10)60483-7 ). 4. L\u00f6nnroth K, Jaramillo E, Williams BG, Dye C, Raviglione M. Drivers of tuberculosis epidemics: the role of risk factors and social determinants. Soc Sci Med. 2009;68(12):2240\u20136 ( https://doi.org/10.1016/j.socscimed.2009.03.041 ). 5. Franco JVA, Bongaerts B, Metzendorf MI, RIsso A, Guo Y, Pena Silva L et al. Undernutrition as a risk factor for tuberculosis disease. Cochrane Database of Systematic Reviews 2024, Issue 6. Art. No.CD015890. (https://doi.org/10.1002/14651858.CD015890.pub2).", "57 TABLE A5.1 TB-SDG monitoring framework: indicators to monitor within SDG 3 SDG 3: Ensure healthy lives and promote well-being for all at all ages SDG TARGETS FOR 2030 SDG INDICATORS ALTERNATIVE INDICATORS TO MONITOR RATIONALE DATA SOURCE COLLECT DATA FOR TB PATIENTS SPECIFICALLY? 3.3 End the epidemics of AIDS, TB, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases 3.3.1 Number of new HIV infections per 1000 uninfected population 3.3.2 TB incidence per 100 000 population HIV prevalence HIV is a strong risk factor for development of TB disease and is associated with poorer treatment outcomes. HIV prevalence is selected in preference to HIV incidence because it is directly measured. UNAIDS WHO Yes, already routinely collected. NA 3.4 Reduce premature mortality by one third from non-communicable diseases and promote mental health and well- being 3.4.1 Mortality rate attributed to cardiovascular disease, cancer, diabetes or chronic respiratory disease Prevalence of diabetes Diabetes is a strong risk factor for development of TB disease, although a link with TB incidence at the national (as opposed to individual) level has been difficult to establish due to confounding. Diabetes prevalence is more relevant than mortality for TB since it directly influences the risk of developing TB. WHO Could be considered at country level, to inform planning of care for comorbidities. 3.5 Strengthen prevention and treatment of substance abuse, including narcotic drug abuse and harmful use of alcohol 3.5.2 Alcohol consumption per capita per year (in litres of pure alcohol) among those aged \u226515 years (harmful level defined nationally) Prevalence of alcohol use disorders Alcohol use is a strong risk factor for TB disease and poorer treatment outcomes at the individual level, although a link with TB incidence at the national (as opposed to individual) level has been hard to establish due to confounding. The prevalence of alcohol use disorders is the most relevant indicator in the context of TB. WHO Could be considered at country level, to inform planning of care for comorbidities. 3.8 Achieve Universal Health Coverage (UHC), including financial risk protection, access to quality essential health- care services and access to safe, effective, quality and affordable essential medicines and vaccines for all 3.8.1 Coverage of essential health services (defined as the average coverage of essential services based on 16 tracer interventions). 3.8.2 Proportion of population with large household expenditures on health as a share of total household", "expenditure or income NA NA Achieving UHC is required to achieve the three high-level targets of the End TB Strategy for reductions in the TB incidence rate, reductions in the number of TB deaths and elimination of catastrophic total costs for TB- affected households (defined as >20% of household income). WHO TB treatment coverage has been monitored for years and is one of the 14 tracer indicators that have been selected to measure SDG indicator 3.8.1. There is a TB-specific indicator that is complementary to 3.8.2 (see Box 3 of the main report). 3.a Strengthen implementation of the WHO Framework Convention on Tobacco Control 3.a.1 Age-standardized prevalence of current tobacco use among those aged \u226515 years Prevalence of smoking among those aged \u226515 years (%) Smoking is a strong risk factor for TB disease at the individual level, although a link with TB incidence at the national (as opposed to individual) level has been difficult to establish due to confounding. WHO Could be considered (e.g. to inform access to smoking cessation interventions). 3.c Substantially increase health financing and the recruitment, development, training and retention of the health workforce in developing countries, especially in least developed countries and small island developing States 3.c.1 Health worker density and distribution Current health expenditure per capita Health expenditure per capita is negatively correlated with TB incidence. WHO No AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus; NA, not applicable; SDG, Sustainable Development Goal; TB, tuberculosis; UHC, universal health coverage; UNAIDS, Joint United Nations Programme on HIV/AIDS; WHO, World Health Organization. Annex 5. The WHO TB-SDG monitoring framework", "58 Global tuberculosis report 2025 TABLE 8.2B TB-SDG monitoring framework: indicators to monitor beyond SDG 3 SDG 1: End poverty in all its forms everywhere SDG TARGETS FOR 2030 SDG INDICATORS ALTERNATIVE INDICATORS TO MONITOR RATIONALE DATA SOURCE COLLECT DATA FOR TB PATIENTS SPECIFICALLY? 1.1 Eradicate extreme poverty for all people everywhere, currently measured as people living on less than $1.25 a day 1.3 Implement nationally appropriate social protection systems and measures for all, including floors, and achieve substantial coverage of the poor and vulnerable 1.1.1 Proportion of population living below the international poverty line 1.3.1 Proportion of population covered by social protection floors/ systems NA NA Poverty is a strong risk factor for TB, operating through several pathways. Reducing poverty should also facilitate prompt health-care seeking. Countries with higher levels of social protection have lower TB burden. Progress on both indicators will help to achieve the End TB Strategy target to eliminate catastrophic costs for TB patients and their households. UN SDG database, World Bank No Could be considered (e.g. to facilitate access to social protection). SDG 2: End hunger, achieve food security and improved nutrition and promote sustainable agriculture 2.1 End hunger and ensure access by all people, in particular the poor and people in vulnerable situations, including infants, to safe, nutritious and sufficient food year- round 2.1.1 Prevalence of undernourishment Prevalence of undernutrition among those aged \u226518 years (%) Prevalence of undernutrition among those aged \u226518 years (%). A recent systematic review published in 2024 has provided estimates of the relative risk of TB among people with and without undernutrition (defined as a body mass index of <18.5 kg/m 2 among those aged \u226518 years). WHO Should be considered (e.g. weight collected from all TB patients to inform the need for nutritional support). SDG 7: Ensure access to affordable, reliable, sustainable, and modern energy for all 7.1 Ensure universal access to affordable, reliable and modern energy services 7.1.2 Proportion of population with primary reliance on clean fuels and technology NA Indoor air pollution is a risk factor for TB disease at the individual level. There has been limited study of ambient air pollution but it is plausible that it is linked to TB incidence. WHO No SDG 8: Promote sustained, inclusive and sustainable economic growth, full and productive employment and decent work for all 8.1 Sustain per capita growth in accordance with national circumstances and, in particular,", "at least 7% GDP growth per year in the least developed countries 8.1.1 Annual growth rate of real GDP per capita GDP per capita Historic trends in TB incidence are closely correlated with changes in the absolute level of GDP per capita (but not with the growth rate). World Bank No SDG 10: Reduce inequality within and among countries 10.1 Achieve and sustain income growth of the bottom 40% of the population at a rate higher than the national average 10.1.1 Growth rates of household expenditure or income per capita, overall and for the bottom 40% of the population Gini index for income inequality TB is a disease of poverty. Decreasing income inequalities combined with economic growth should have an effect on the TB epidemic. World Bank OECD No SDG 11: Make cities and human settlements inclusive, safe, resilient and sustainable 11.1 Ensure access for all to adequate, safe and affordable housing and basic services and upgrade slums 11.1.1 Proportion of urban population living in slums, informal settlements or inadequate housing NA Living in a slum is a risk factor for TB transmission due to its link with overcrowding. It is also a risk factor for developing TB disease, due to links with air pollution and undernutrition. UN SDG database No GDP, gross domestic product; NA, not applicable; OECD, Organisation for Economic Co-operation and Development; SDG, Sustainable Development Goal; TB, tuberculosis; UN, United Nations; WHO, World Health Organization.", "WHO operational handbook on tuberculosis. Module 2: screening - systematic screening for tuberculosis disease ISBN 978-92-4-002261-4 (electronic version) ISBN 978-92-4-002262-1 (print version) \u00a9 World Health Organization 2021 Some rights reserved. 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The risk of claims resulting from infringement of any third party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific", "companies or of certain manufacturers\u2019 products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout by Inis Communication", "iii Contents Acknowledgements v Abbreviations and acronyms vii Definitions viii Chapter 1. Introduction 1 1.1 Rationale for systematic screening for TB disease 1 1.2 Principles of TB screening 3 1.3 Objectives of the operational handbook 4 1.4 Target audience of the operational handbook 6 Chapter 2. The six steps in the planning and implementation cycle 7 2.1 Introduction 7 2.2 Assessing the situation 9 2.3 Setting goals and specific objectives 15 2.4 Identifying and prioritizing risk groups 16 2.5 Choosing algorithms for screening and diagnosis 22 2.6 Planning, budgeting and implementing 22 2.7 Monitoring, evaluating and modifying the programme 25 Chapter 3. Screening tools and algorithms 29 3.1 Screening tools 29 3.2 Algorithms for screening 35 3.3 ScreenTB tool 39", "iv Chapter 4. Implementation of CAD technologies in a new setting 41 4.1 Considerations in selecting and using CAD for screening in TB programmes 41 4.2 Toolkit for CAD calibration to enable implementation 43 4.3 Online tool for calibration of CAD in a new setting 43 Chapter 5. Screening for tuberculosis disease among adults and adolescents living with HIV 45 5.1 Introduction 45 5.2 Screening tools 46 5.3 Considerations for use of all screening tools 50 5.4 Algorithms for screening 52 Chapter 6. Screening for tuberculosis disease in children 53 6.1 Introduction 53 6.2 Screening child contacts of patients with TB 53 6.3 Screening children living with HIV 56 6.4 Algorithms for screening 57 References 59 Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 63 Annex 2 Comparative performance of algorithms for the general population and high-risk groups (not including people living with HIV) 75 Annex 3 Screening algorithms for adults and adolescents living with HIV 79 Annex 4 Comparative performance of algorithms for adults and adolescents living with HIV 91 Annex 5 Screening algorithms for children 93", "Acknowledgements v Acknowledgements This operational handbook was prepared by Saskia den Boon and Cecily Miller, with input from Dennis Falzon and Matteo Zignol, under the overall direction of T ereza Kasaeva, Director, WHO Global T uberculosis Programme. The WHO Global T uberculosis Programme gratefully acknowledges the contributions of all experts and reviewers involved in the production of the latest update of the WHO guidelines on systematic screening for TB disease, on which this handbook is based, as well as other contributors listed below. The handbook was funded by grants provided to WHO by USAID and the Russian Federation. Peer reviewers of this handbook T eeb Al-Samarrai (US President\u2019s Emergency Plan for AIDS Relief), Mirjam Bakker (Royal T ropical Institute, Netherlands), David Branigan (T reatment Action Group, United States of America), Macarthur Charles (US Centers for Disease Control and Prevention), Charlotte Colvin (US Agency for International Development), Jacob Creswell (Stop TB Partnership, Switzerland), Christopher Gilpin (International Organization for Migration, Switzerland), Jeremy Hill (KNCV , Netherlands), Kobto Ghislain Koura (The Union, France) Alena Skrahina (National TB Programme, Belarus), Marieke van der Werf (European Centre for Disease Prevention and Control, Sweden). Other contributors The Guideline Development Group comprised Denise Arakaki-Sanchez (Ministry of Health, Brazil), Omolola Atalabi (University College Hospital (Ibadan), Nigeria), Helen Ayles (Infectious Diseases and International Health, London School of Hygiene & T ropical Medicine, Zambia), David Branigan (T reatment Action Group, USA), Jeremiah Chakaya (The Union, Kenya), Gavin Churchyard (The Aurum Institute, South Africa), Elizabeth Corbett (Liverpool School of T ropical Medicine and Hygiene, Malawi), Anand Date (Centers for Disease Control and Prevention, USA), Esty Febriani (Civil Society T ask Force, Indonesia), Celine Garfin (National TB Programme, Philippines), Amir M Khan (Association for Social Development, Pakistan), Katharina Kranzer (London School of Hygiene & T ropical Medicine, United Kingdom of Great Britain and Northern Ireland), T amara Kredo (University of Cape T own, South Africa), Knut L\u00f6nnroth (Karolinska Institute, Sweden), Guy Marks (University of Sydney, Australia), Andrey Maryandyshev (Northern State Medical University, Russian Federation), David Mungai (Civil Society T ask Force, Kenya), Iveta Ozere (Centre of T uberculosis and Lung Diseases, Latvia), Alena Skrahina (National TB Programme, Belarus) and Marieke J. van der Werf (European Centre for Disease Prevention and Control, Sweden). Jeremiah Chakaya and T amara Kredo co-chaired the meetings of the Guideline Development Group. Holger Sch\u00fcnemann (McMaster University, Canada) served as technical resource person for GRADE methodology. The following people", "participated as observers in the Guideline Development Group meetings: Sevim Ahmedov and Charlotte Colvin (US Agency for International Development, USA), Draurio Barreira Cravo Neto (UNITAID, Switzerland), Olivia Bierman (Karolinska Institute, Sweden), Michael Campbell (Clinton Health Access Initiative, USA), Pierre-Marie David (Universit\u00e9 de Montr\u00e9al, Canada), Brian Kaiser (Global Drug Facility, Switzerland), Christopher Gilpin (International Organization for Migration, Switzerland) and Mohammed Y assin (Global Fund to Fight AIDS, TB and Malaria, Switzerland). Kerri Viney (WHO Global T uberculosis Programme) contributed to the reviews on the accuracy of screening approaches in the general population. Corinne Merle, Vanessa Veronese and Debora Pedrazzoli of the Special Programme for Research and T raining in T ropical Diseases (TDR)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease vi contributed to the development of the computer-aided detection (CAD) toolkit described in section 4. Emanuele Pontali and Elizabeth Harausz were involved in preparing first drafts of sections 5 and 6, respectively. Annabel Baddeley contributed to Chapter 5 and Sabine Verkuijl to Chapter 6. Nazir Ismail and Alexei Korobitsyn (WHO Global T uberculosis Programme) and Rajendra Y adav (WHO Philippines) reviewed the handbook. Zhi Zhen Qin (Stop TB Partnership, Geneva) contributed to the section on CAD and Christina Y oon (University of California at San Francisco, USA) to the section on C-reactive protein (CRP). Christopher Dobosz designed the algorithm figures. The academic groups that reviewed the evidence for the 2021 update of the TB screening guidelines are also acknowledged (full list included in the guidelines document). The WHO Global T uberculosis Programme also thanks the Guideline Review Committee and its WHO secretariat for reviewing and approving the guidelines and the staff of the WHO department of Quality Assurance of Norms and Standards for their support in finalizing this handbook. The operational handbook was edited by Elisabeth Heseltine.", "Abbreviations and acronyms vii Abbreviations and acronyms ART antiretroviral treatment CAD computer-aided detection of TB-related abnormalities on chest radiography CXR chest radiograph (chest X-ray) LF-LAM lateral flow urine lipoarabinomannan assay mWRD molecular WHO-recommended rapid diagnostic test NNS number needed to screen ROC receiver operating characteristic TB tuberculosis TPT TB preventive treatment W4SS WHO-recommended four-symptom screen", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease viii Definitions Active (TB) case-finding: Provider-initiated screening and testing in communities by mobile teams, often using mobile X-ray and rapid molecular tests. The term is sometimes used synonymously with \u201csystematic screening\u201d. It is referred to as \u201cintensified case-finding\u201d when conducted in health-care facilities and as \u201cenhanced case-finding\u201d when conducted in communities. Close contact: A person who does not live in the household but who shared an enclosed space, such as a social gathering place, workplace or facility, with the index patient for extended periods during the day during the 3 months before the current disease episode commenced. Computer-aided detection (CAD): refers to the use of specialized software to interpret abnormalities on chest radiographs that are suggestive of TB. The results are expressed as abnormality scores. CAD may be used for screening or triage. Contact: Any person who has been exposed to a person with TB disease. Contact investigation: systematic identification of people with previously undiagnosed TB disease and TB infection among the contacts of an index TB patient in the household and in comparable settings in which transmission occurs. It consists of identification, clinical evaluation and/or testing and provision of appropriate anti-TB therapy (for people with confirmed TB) or TB preventive treatment (for those without TB disease). This term is often used synonymously with \u201ccontact tracing\u201d; however, in the context of TB, action beyond identifying contacts is critical. Household contact: A person who shared the same enclosed living space for one or more nights or for frequent or extended periods during the day with the index patient during the 3 months before the start of current treatment. Index patient (index case): A person of any age with new or recurrent TB initially identified in a specific household or comparable setting in which others may have been exposed. An index patient is the person on whom a contact investigation is centred but is not necessarily the source. Initial screening: The first screening test, examination or other procedure applied in a population eligible for screening. Number needed to screen: The number of persons that need to undergo screening in order to diagnose one person with of TB disease. Passive TB case-finding: A patient-initiated pathway to TB diagnosis involving: (1) a person with TB disease who experiences symptoms that he or she recognizes as serious; (2) the person having access to and seeking", "care and presenting spontaneously at an appropriate health facility; (3) a health worker correctly assessing that the person fulfils the criteria for presumptive TB; and (4) successful use of a diagnostic algorithm with sufficient sensitivity and specificity to diagnose TB. Patient-initiated health care pathway: The patient-initiated pathway to TB diagnosis relies on patients seeking care and on health systems to respond quickly and appropriately. Some people may access care after exposure if they are very well informed, but most people will seek care only once they experience symptoms severe enough to merit attention. They may experience delay due to access barriers. On accessing care, they may experience delays until they are referred to a service that can make a TB diagnosis, and there may be further delays and barriers before a diagnosis is made and appropriate treatment is initiated.", "Definitions ix Provider-initiated TB screening pathway: The provider-initiated TB screening pathway systematically targets people at high risk of exposure or of developing TB disease and screens them by assessing symptoms, using tests, examinations or other procedures to identify those who might have TB, following up with a diagnostic test and additional clinical assessments to make a definite diagnosis. This approach can target people at different stages of TB, for example by screening those at high risk of exposure (e.g. high TB burden communities or settings such as prisons) or those who are exposed to TB (e.g. contacts of a TB patient), or those who have high risk of developing TB (e.g. people living with HIV). Screening programmes must include an appropriate pathway for diagnostic confirmation, treatment and care and further management. Repeat screening: Re-screening in the same population at a given interval. Risk group: Any group of people in which the prevalence or incidence of TB is significantly higher than in the general population. Screening test, examination or procedure for TB: Used to distinguish people with a high likelihood of having TB disease from people who are highly unlikely to have TB. A screening test is not intended to be diagnostic. People with positive results on a screening test should undergo further evaluation, depending on the screening algorithm used. Systematic screening for TB disease: Systematic identification of people at risk for TB disease in a predetermined target group by assessing symptoms and using tests, examinations or other procedures that can be applied rapidly. For those who screen positive, the diagnosis needs to be established by one or several diagnostic tests and additional clinical assessments. This term is sometimes used interchangeably with \u201cactive tuberculosis case finding\u201d. It should be distinguished from testing for TB infection (with a TB skin test or interferon-g release assay). Triage: The process of deciding the diagnostic and care pathways for people, based on their symptoms, signs, risk markers, and test results. T riaging involves assessing the likelihood of various differential diagnoses as a basis for making clinical decisions. It can follow more-or-less standardized protocols and algorithms and may be done in multiple steps. Triage test for TB: A test that can be conducted rapidly in people presenting to a health facility to differentiate those who should undergo further diagnostic evaluation for TB from those who should undergo other further investigation for non-TB diagnoses. Tuberculosis (TB): The", "disease state caused by Mycobacterium tuberculosis. It is usually characterized by clinical manifestations, which distinguishes it from TB infection without signs or symptoms. In this document, it is referred to simply as \u201cTB\u201d or \u201cTB disease\u201d. It should be distinguished from \u201cTB infection\u201d (previously referred to as \u201clatent TB infection\u201d or LTBI, a term that incorporated generations of TB bacilli that are not dormant). Pulmonary TB involves the lungs and is the most common form of TB. Extrapulmonary TB involves organs other than the lungs (e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones or meninges). The two forms may coexist in the same patient. Tuberculosis preventive treatment: T reatment offered to individuals considered to be at risk of TB disease in order to reduce that risk. Also referred to as \u201ctreatment of TB infection\u201d and previously treatment of \u201clatent TB infection\u201d. WHO four-symptom screen: The presence of either cough, fever, weight loss or night sweats used as a screening test in people living with HIV .", "Chapter 1. Introduction 1 Chapter 1. Introduction 1.1 Rationale for systematic screening for TB disease T uberculosis (TB) is a major yet preventable airborne infectious disease. About one fourth of the world\u2019s population is infected with TB bacilli, the vast majority of whom have no disease (1, 2). In 2019, an estimated 10 million new TB cases emerged worldwide, and more than 1.4 million people died of TB, making it the leading single infectious disease cause of death that year (2). Of the estimated 10 million people who fell ill with TB in 2019, TB was not diagnosed in an estimated 2.9 million, and they were not enrolled in quality-assured TB treatment (2). Additionally, many people delay seeking care for their illness or are misdiagnosed before they are eventually diagnosed and treated (3) (see also Web Annex B of the screening guidelines). The aim of screening (or active TB case finding) is to detect TB disease early in order to minimize avoidable delays in diagnosis and initiation of treatment, thereby reducing the risk of unfavourable treatment outcomes, health sequelae and the adverse social and economic consequences of TB for individuals and their families. In addition, screening reduces TB transmission in a household, workplace, school or other community setting by removing people with prevalent disease and shortening the duration of infectiousness. This reduces the incidence of TB infection and consequently the incidence and prevalence of TB disease. When implemented with an effective algorithm for screening and diagnostic testing and when integrated with TB preventive treatment (TPT) for people without TB disease at risk of progression, there is a higher likelihood that the health of individuals and the community will be improved. T esting for TB infection with a TB skin test or interferon-g release assay to inform decisions about TPT is not part of screening and is discussed in separate normative documents (4, 5). Detecting TB only among people who present to health facilities is not enough to find all people with TB disease. The remaining case-detection gap, particularly in certain vulnerable populations, and the persistence of diagnostic delays and resulting continued transmission in the community, indicate the need for a more active approach to early detection of TB. This justifies systematic screening of selected risk groups and populations for TB disease. The WHO End TB Strategy includes systematic screening for TB disease in high-risk groups as a central component of", "its first pillar, to ensure early diagnosis of all persons with TB (6, 7). In 2021, WHO has updated the TB screening guidelines from 2013 to help countries in implementing this critical programmatic component. This operational handbook accompanies WHO consolidated guidelines on tuberculosis. Module 2: screening \u2013 systematic screening for tuberculosis disease and provides additional practical details for applying the guideline recommendations by identifying priority risk groups and selecting the appropriate screening approaches in the light of new evidence. The updated recommendations are summarized in T able 1.1.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 2 Table 1.1 Recommendations in the WHO consolidated guidelines on tuberculosis. Module 2: screening \u2013 systematic screening for tuberculosis disease, 2021 Screening for TB in targeted populations 1 Systematic screening for TB disease may be conducted among the general population in areas with an estimated TB prevalence of 0.5% or higher (updated recommendation: conditional recommendation, low certainty of evidence). 2 Systematic screening for TB disease may be conducted among subpopulations with structural risk factors for TB. These include urban poor communities, homeless communities, communities in remote or isolated areas, indigenous populations, migrants, refugees, internally displaced persons and other vulnerable or marginalized groups with limited access to health care (existing recommendation: conditional recommendation, very low certainty of evidence). 3 People living with HIV should be systematically screened for TB disease at each visit to a health facility (existing recommendation: strong recommendation, very low certainty of evidence). 4 Household contacts and other close contacts of individuals with TB disease should be systematically screened for TB disease (updated recommendation: strong recommendation, moderate certainty of evidence). 5 Systematic screening for TB disease should be conducted in prisons and penitentiary institutions (updated recommendation: strong recommendation, very low certainty of evidence). 6 Current and former workers in workplaces with silica exposure should be systematically screened for TB disease (existing recommendation: strong recommendation, low certainty of evidence). 7 In settings where the TB prevalence in the general population is 100/100 000 population or higher, systematic screening for TB disease may be conducted among people with a risk factor for TB who are either seeking health care or who are already in care (existing recommendation: conditional recommendation, very low certainty of evidence). 8 People with an untreated fibrotic lesion seen on chest X-ray may be systematically screened for TB disease (existing recommendation: conditional recommendation, very low certainty of evidence). Tools for screening for TB 9 Among individuals aged 15 years and older in populations in which TB screening is recommended, systematic screening for TB disease may be conducted using a symptom screen, chest X-ray or molecular WHO-recommended rapid diagnostic tests, alone or in combination (new recommendation: conditional recommendation, very low certainty of evidence for test accuracy). 10 Among individuals aged 15 years and older in populations in which TB screening is recommended, computer-aided detection software programmes may be used in place of human readers for interpreting digital chest", "X-rays for screening and triage for TB disease (new recommendation: conditional recommendation, low certainty of evidence). 11 Among adults and adolescents living with HIV , systematic screening for TB disease should be conducted using the WHO-recommended four symptom screen and those who report any one of the symptoms of current cough, fever, weight loss or night sweats may have TB and should be evaluated for TB and other diseases (existing recommendation: strong recommendation, moderate certainty of evidence).", "Chapter 1. Introduction 3 12 Among adults and adolescents living with HIV , C-reactive protein using a cut-off of >5mg/L may be used to screen for TB disease (new recommendation: conditional recommendation, low certainty of evidence for test accuracy). 13 Among adults and adolescents living with HIV , chest X-ray may be used to screen for TB disease (new recommendation: conditional recommendation, moderate certainty of evidence for test accuracy). 14 Among adults and adolescents living with HIV , molecular WHO-recommended rapid diagnostic tests may be used to screen for TB disease (new recommendation: conditional recommendation, moderate certainty of evidence for test accuracy). 15 Adult and adolescent inpatients with HIV in medical wards where the TB prevalence is > 10% should be tested systematically for TB disease with a molecular WHO-recommended rapid diagnostic test (new recommendation: strong recommendation, moderate certainty of evidence for test accuracy). 16 Among individuals younger than 15 years who are close contacts of someone with TB, systematic screening for TB disease should be conducted using a symptom screen including any one of cough, fever or poor weight gain; or chest radiography; or both (new recommendation: strong recommendation, moderate to low certainty of evidence for test accuracy). 17 Among children younger than 10 years who are living with HIV , systematic screening for TB disease should be conducted using a symptom screen including any one of current cough, fever, poor weight gain or close contact with a TB patient (new recommendation: strong recommendation, low certainty of evidence for test accuracy). TB: tuberculosis. 1.2 Principles of TB screening Systematic screening for TB fulfils the classic screening criteria (8). The following key principles are to be considered in planning a TB screening initiative: \u2022 Principle 1: TB screening should always be done with the intention to follow up with appropriate medical care and ideally implemented where high-quality TB diagnostic and treatment services are available. If a community lacks access to appropriate follow-up care but would benefit from TB screening, this should be an impetus for investment by national TB programmes in TB diagnosis and treatment services, in order to complement TB screening. \u2022 Principle 2: Screening should reach the people at greatest risk of developing TB disease, including high-risk groups and communities with a high prevalence of TB. Prioritization of risk groups for screening should be based on an assessment for each group of the potential benefits and harm, the", "feasibility and acceptability of the screening approach, the number needed to screen (NNS) and the cost\u2013effectiveness of screening. The benefits and harm of TB screening in different groups and populations need to be carefully assessed to maximize the common good while minimizing harm to individuals. TB threatens the health not only of an affected individual but also of their communities and the broader population. \u2022 Principle 3: TB screening should follow established ethical principles for screening for infectious diseases, including obtaining voluntary informed consent before proceeding with screening individuals and observing human rights, and be designed to minimize the risks of discomfort, pain, stigmatization and discrimination. Informed consent is a basic right and an important means of respecting an individual\u2019s autonomy.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 4 \u2022 Principle 4: The choice of algorithm for screening and diagnosis is based on an assessment of the accuracy of the algorithm for each risk group, as well as the availability, feasibility and cost of the screening tests. After a positive screening test result, the diagnosis of TB should be confirmed before TB treatment is started. \u2022 Principle 5: TB screening should be synergized with the delivery of other health and social services. Synergies are best identified during the development and implementation of screening approaches for different target populations, which may have particular patterns of use of health and social services. \u2022 Principle 6: A screening strategy is expected to maximize coverage and frequency of screening to achieve its aims. Regular monitoring is necessary to inform any re-prioritization of risk groups, resource use, adaptation of screening approaches and discontinuation of screening. This includes the assessment of risk of false-positive diagnoses resulting from screening. 1.3 Objectives of the operational handbook This document provides practical guidance on translating WHO\u2019s recommendations for screening into a national or local strategy with clear objectives, prioritization of risk groups and definition of the most appropriate screening approaches. The specific objectives are: \u2022 to support Member States in implementing effective TB screening by supporting policymakers in ministries of health in choosing the best approach to planning and implementing screening and active case-finding, depending on the context; \u2022 to provide a sound basis for development or updating of national guidelines for TB screening according to the epidemiology of TB in different risk groups and the health care delivery system in the country; and \u2022 to contribute to finding people with TB who may be missed by standard case-finding approaches and finding people with TB earlier in the course of disease to reduce transmission, morbidity, mortality and financial hardship for people suffering from TB. Six essential steps in the cycle of designing and implementing a TB screening programme are discussed in Chapter 2: 1) assessing the situation; 2) setting goals and specific objectives; 3) identifying and prioritizing risk groups; 4) choosing algorithms for screening and diagnosis; 5) planning, budgeting and implementing and 6) monitoring, evaluating and modifying the programme. These six steps are an iterative process, which may lead to revision of the strategy, as necessary. The process should be followed throughout screening and integrated with overall national", "Chapter 1. Introduction 5 Fig. 1.1 The six essential steps in the cycle of designing and implementing a TB screening programme Choosing algorithms for screening and diagnosis Planning, budgeting and implementing Monitoring, evaluating, and modifying the programme Setting goals and specific objectives Assessing the situation Identifying and prioritizing risk groups SIX STEPS OF THE SCREENING IMPLEMENTATION CYCLE 2 3 4 5 6 1 Details of different screening tools and their performance in different populations and of algorithms for screening and diagnosis are described in Chapter 3. Most of the approaches proposed in this handbook are for detecting pulmonary TB, the predominant form of the disease worldwide, which is directly transmissible and for which most evidence exists. This does not diminish the importance of extrapulmonary TB as a public health concern in many countries and in certain subpopulations (e.g. children). About 16% of new and relapsed TB patients reported globally in 2019 had exclusively extrapulmonary forms of TB, presenting an additional challenge for detection. Screening for extrapulmonary TB is therefore an important gap that should be filled by research and guidance. The screening tools described here include assessment of symptoms and chest X-ray (CXR), which have traditionally been used for TB screening, and tools that are newly recommended for screening, including computer-aided detection (CAD) technologies for automated interpretation of digital CXR, C-reactive protein (CRP) for screening people living with HIV and use of WHO-recommended rapid molecular diagnostic tests (mWRDs) for screening. Algorithms that combine various screening and diagnostic tools in order to optimize accuracy and ensure a feasible implementation strategy are also discussed. As algorithms perform differently in different populations, an online tool, ScreenTB,", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 6 has been developed to assist in prioritizing risk groups for screening and choice of algorithm. It is described in Chapter 3. CAD software packages for automated interpretation of digital CXR images of TB are recommended for screening for the first time by WHO. Chapter 4 provides suggestions on implementation of CAD technologies in new settings, including selection of CAD technologies and protocols for operational research to facilitate implementation. This chapter also provides a description of an online tool, CAD for TB, for the analysis and interpretation of data for CAD calibration. Chapter 5 specifically addresses TB screening in people living with HIV , describing the different subpopulations (outpatients receiving antiretroviral treatment (ART), outpatients newly enrolling in ART care, inpatients with HIV and pregnant women living with HIV), who have specific needs and in whom screening tests perform differently. Because new screening tools are recommended for TB screening in people living with HIV , including CRP and mWRD, specific consideration is given to how these tools and associated algorithms might be integrated into HIV services with additional tests like lateral flow urine lipoarabinomannan assay (LF-LAM) for people with advanced disease. Chapter 6 addresses operational factors specific to the new recommendations on screening in children, including a discussion of implementation specifically for different subpopulations of children by age group and risk population. 1.4 Target audience of the operational handbook The operational handbook is intended for personnel in national TB programmes and national HIV/ AIDS programmes, or their equivalents, and other relevant national health programmes in ministries of health; other relevant ministries working in public health and screening; other health policy-makers, implementing partners including technical and funding agencies, civil society and representatives of affected communities, clinicians and public health practitioners working on TB and HIV and infectious diseases in the public and private sectors.", "Chapter 2. The six steps in the planning and implementation cycle 7 Chapter 2. The six steps in the planning and implementation cycle 2.1 Introduction The two complementary approaches for improving early detection of TB are illustrated in Fig. 2.1 The primary approach is to optimize the patient-initiated pathway to TB diagnosis and treatment (for details see 2.1.1). This approach does not constitute screening and is a passive form of case detection. Because it relies on initiation by people with TB disease and on health systems to respond, this approach is beset with delays associated with societal norms, stigmatization and discrimination, illness behaviour, limitations in health coverage, barriers to accessing services, and constraints of resources and capacity at health service entry points and referral pathways within the health system. The other approach to enhance case detection is screening, or the provider-initiated screening pathway to TB diagnosis and is the focus of this operational handbook. Fig. 2.1 Comparison of the provider-initiated TB screening pathway with the patient- initiated health care pathway for TB Patient-initiated pathway Provider-initiated screening pathway TB diagnosisSymptomatic TB disease Asymptomatic TB diseaseInfectedExposed Access care Navigate health system Referred to TB service At risk TB treatment and notification TB screening", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 8 2.1.1 Enhancing the patient-initiated pathway to TB diagnosis The patient-initiated pathway to TB diagnosis can be enhanced by: \u2022 improving access to care , including reducing the direct and indirect costs to patients associated with seeking care and addressing the specific needs of vulnerable groups by strengthening primary health-care services, extending diagnostic and testing services and providing social protection schemes where possible and necessary. \u2022 improving the acceptability of care , by ensuring privacy and providing fast-tracking through outpatient departments and faster services to reduce waiting times and to ensure that daily wage- earners do not lose income. Incorporating \u201ccare\u201d aspects, by including emotional care in addition to diagnosis and treatment in training curricula help to ensure empathetic, compassionate and patient-centred care (9). \u2022 community engagement and demand generation, by education and awareness campaigns (including on exposure and risk) for the general public and in communities that are at higher risk of TB to increase the likelihood that those who have been exposed and/or have TB disease will seek care at facilities with the capacity to diagnose and treat TB. \u2022 training and capacity-building of health-care workers, by providing additional training and equipping all health-care workers in the health system, in both the public and the private sectors, in primary care, at entry points to health care and lay community workers and volunteers (10) to increase the likelihood that individuals with symptoms of TB who seek care are recognized and referred for appropriate evaluation and care. \u2022 reassessing the definition of a person with possible TB, by broadening the indications for diagnostic testing for TB, in accordance with the local epidemiology of the disease and the epidemiology of the most common risk factors for TB to help ensure that the appropriate people are targeted for evaluation. \u2022 improving access to testing and diagnostics, by increasing the capacity of mWRDs, ensuring sufficient laboratory requirements, including human resources, improving links between the private and public sectors and improving the system of reporting results from the laboratory to the clinician. \u2022 making any other changes to current approach to passive case detection , as such changes may result in more patients identified in facilities. Greater use of CXR, mWRDs and other accurate tools for diagnosing TB may increase the number of people with TB detected. Additional approaches to increasing the capacity for", "TB care and prevention include: \u2022 improving the integrated management of respiratory conditions in primary health care (11); \u2022 scaling up mWRD testing (e.g. Xpert MTB/RIF, T ruenat MTB and MTB-RIF Dx) (12, 13); \u2022 scaling up sputum collection and transport systems; \u2022 improving the diagnosis of bacteriologically negative TB, extrapulmonary TB and TB in children; \u2022 providing access to CXR services and CAD; and \u2022 improving referrals and notifications by all care providers (10). 2.1.2 The provider-initiated screening pathway to TB diagnosis The provider-initiated screening pathway to TB diagnosis entails systematic identification of people with possible TB disease in a predetermined target group with tests, examinations or other procedures that can be applied rapidly. In those with a positive screening test result, the diagnosis must be established by one or several diagnostic tests and additional clinical assessments, which together are highly accurate. Provider-initiated systematic screening requires careful planning in order to target the specific characteristics and needs of populations. Key stakeholders should be involved in planning, including district or regional managers, who are often familiar with specific implementation challenges, as well as stakeholders from the groups targeted for screening, to create a more people-centred approach (14).", "Chapter 2. The six steps in the planning and implementation cycle 9 Screening in low-risk groups has the potential to cause more harm than benefit \u2013 for example, by detecting more false-positive cases than true-positive cases and potentially overwhelming a stretched diagnostic service and diverting resources for more likely and symptomatic cases. Therefore, after relevant risk groups that potentially would benefit from screening have been identified, those groups at the highest risk should be prioritized. It is also necessary to choose the appropriate screening and diagnostic tests and algorithms for each risk group and for each epidemiological situation. A systematic, carefully planned approach avoids wasting resources and optimizes individual and public health benefits. 2.2 Assessing the situation The epidemiology of TB in each setting and the social and the health-system contexts will inform decisions on a TB screening strategy, including how risk groups are prioritized, which screening approach to choose and whether screening of specific risk groups is feasible . Therefore, before embarking on detailed planning, a baseline assessment of the following features should be undertaken: \u2022 the existing screening and outreach activities, to assess the potential and readiness for intersectoral collaboration (for details, see 2.2.1); \u2022 the societal context, to assess whether screening in specific communities or risk groups would be feasible, acceptable and valuable to the community (for details, see 2.2.2); \u2022 the epidemiology of TB, to identify gaps in case detection, current case-finding activities and the size and distribution of risk groups that might be targeted for screening (for details, see 2.2.3); \u2022 the national TB programme and the general health-care system, including the private health sector and other nongovernmental providers, to assess their preparedness for screening and their capacity to manage a potential increase in evaluation, diagnosis, monitoring and treatment of patients with TB, providing TPT and referring people with symptoms of other respiratory ailments or health conditions identified during TB screening (for details, see 2.2.4); \u2022 health-care coverage and access to health services, to determine whether all people diagnosed with TB will have equitable access to high-quality care (for details, see 2.2.5); and \u2022 protection from stigmatization, discrimination and harm, to ensure that people do not experience negative consequences from screening or any eventual TB diagnosis and its implications for the rights to employment, education and freedom of movement, among others (for details, see 2.1.6). The specific questions to be addressed in a situation assessment", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 10 Table 2.1 Questions to be addressed in a situation assessment before implementing screening for TB Area to be assessed Questions Existing screening and outreach activities that may allow intersectoral collaboration \u2022 Which populations are already being screened for TB? \u2022 Which other health conditions are already being screened for? \u2022 What links exist among health care services (e.g. integrated TB/HIV services)? \u2022 Do any of the potential collaborating agencies have experience in screening for TB or caring for vulnerable populations? \u2022 Is there infrastructure that could be used for TB screening? \u2022 Where does the funding come from for the other programmes? \u2022 Are there already known locations and trained human resources that can be involved in TB screening? \u2022 Are there social support programmes that could collaborate? Distribution of TB burden and risk factors; size and distribution of gaps in case detection \u2022 What is the current distribution of the estimated TB burden in this setting (as inferred from TB notification and case-finding, prevalence and mortality) and specifically for different subpopulations or risk groups? \u2022 What is the current gap in case detection, and what are the specific causes of missed or delayed diagnosis for each subpopulation or risk group? \u2022 Which subpopulations or risk groups have the highest risk that TB will remain undetected? \u2022 Which subpopulations or risk groups make the greatest contribution to undetected TB? \u2022 What are the differences in gender with regard to TB burden, TB risks and barriers to care? \u2022 Which types of TB are most likely not to be detected? (e.g. extrapulmonary TB) \u2022 What are the main reasons for gaps in case detection? \u2022 What are the HIV burden and ART coverage? Current case- detection activities \u2022 What is the level of knowledge about TB among health-care staff and others who provide care? \u2022 What is the current definition of presumed TB, and to what extent is it applied in practice? \u2022 Which algorithms and diagnostic tests are used to screen for and diagnose different types of TB? \u2022 T o what extent are mWRDs available, and which individuals are eligible? What is the yield in different settings? \u2022 Are CXRs available, and what is the level of access in hospitals, community health centres and mobile health units? Are the CXRs of good quality? Is the interpretation of the", "CXRs of good quality? How are CXRs used for TB screening and diagnosis? \u2022 What is the availability of CAD or the willingness to introduce it for TB detection? \u2022 What is the trend in the number of people being tested for TB, by subpopulation? \u2022 What is the trend in the proportion of people testing positive for TB among those tested, by subpopulation?", "Chapter 2. The six steps in the planning and implementation cycle 11 Area to be assessed Questions Role of different providers \u2022 When do people go to a provider, and what type of provider do they go to? Do people go to public or private providers? \u2022 What diagnosis and treatment services are offered by different providers (for example, in the public and private sectors; among formal or informal providers such as traditional healers; by health-care or other providers; by community or civil society organizations)? \u2022 Are services affordable? TB awareness and health-seeking behaviour \u2022 What barriers prevent access to diagnostic and treatment services for the targeted community? \u2022 What is the level of knowledge about TB disease and TB care in the targeted community? \u2022 What is the level of knowledge about TB risk, transmission, exposure and prevention in the targeted community? \u2022 What are the main reasons for delays in seeking health care in the targeted community? \u2022 What are the perceptions of members of the targeted groups regarding TB services? Risk group size, distribution and special challenges \u2022 What are the sizes and geographical distribution of the different TB risk groups? \u2022 Which specific barriers to accessing care affect the different groups? \u2022 What are the specific challenges to initiating and adhering to treatment in each group? Previous and present experience in improving early TB detection \u2022 What were the results of any previous effort to improve the patient- initiated pathway to ensure earlier detection of TB? \u2022 What were the outcomes and lessons learnt from previous systematic screening initiatives in different risk groups? Stigmatization, discrimination, coverage, access, catastrophic costs \u2022 What are the existing frameworks for protecting human rights, and to what extent are they enforced? \u2022 What sort of stigmatization or discrimination might people screened for TB and people diagnosed with TB experience, what are the possible consequences, and what can be done to mitigate those risks? \u2022 Which groups are at particular risk of stigmatization or discrimination and its consequences, and what can be done to mitigate those risks? \u2022 What is the legal status of migrants screened for TB and/or diagnosed with TB? 2.2.1 Existing screening and outreach activities The cost of screening, especially as an outreach activity, can be high. The opportunity cost must be considered and compared with other means for improving early TB detection, such as improving the patient-initiated pathway", "to TB diagnosis (see 2.1.1). The efficiency of a screening programme can be increased by collaboration with other health and social programmes. Outreach activities such as health promotion, social support or screening the targeted population for other health conditions may already be in place and may serve as platforms for TB screening within a broader, more integrated approach. Identification of appropriate entry points for screening is critical, and this requires mapping the healthcare and social-service providers for relevant groups, such as endocrinology departments caring for people with diabetes or nongovernmental organizations providing social support for", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 12 vulnerable groups. The private health care sector plays an important role in providing services to a large proportion of patients with TB, and, by involving them in TB screening, they may provide an entry point to TB care and treatment that would otherwise not be available. T able 2.2 lists the programmes, services and stakeholders that could collaborate in screening activities. Table 2.2 Services, programmes and stakeholders that could collaborate in systematic screening programmes for TB Services Programmes and stakeholders Health services \u2022 HIV programmes, clinics offering voluntary counselling and testing for HIV , clinics delivering ART, programmes to prevent mother-to-child transmission of HIV \u2022 Diabetes or endocrinology clinic screening initiatives, within the broader platform for preventing noncommunicable diseases \u2022 Maternal and child health and antenatal care programmes \u2022 Immunization clinics and campaigns and vaccination programmes \u2022 Smoking and alcohol cessation programmes \u2022 Malnutrition treatment programmes \u2022 Clinics and outreach programmes for people who use or inject drugs \u2022 Dialysis centres \u2022 Infection control providers and programmes, e.g. COVID-19 screening programmes \u2022 Community health services and outreach services such as community health workers and volunteers, or community health posts, including those run by community or civil society organizations or nongovernmental organizations \u2022 Other (community) screening programmes, such as for HIV , sexually transmitted infections, visceral leishmaniasis, or leprosy Social services \u2022 Outreach and community support or development programmes in remote rural areas or poor urban communities \u2022 Programmes and institutions that support homeless people or house insecure individuals and families or other vulnerable populations \u2022 Programmes that provide social support for sex workers \u2022 Programmes that provide social services for immigrants and refugees \u2022 Social protection programmes for youth, orphans or other vulnerable populations \u2022 Programmes that address food insecurity \u2022 Other partner agencies working with affected or vulnerable populations Other government services \u2022 Prison health services \u2022 Military \u2022 Occupational health services (especially for miners, health-care workers and workers in other high-risk occupations) \u2022 One Health initiatives Civil society organizations \u2022 Nongovernmental organizations and others that provide social support for vulnerable groups Private health- care providers \u2022 Private providers \u2022 Informal providers \u2022 Pharmacies", "Chapter 2. The six steps in the planning and implementation cycle 13 2.2.2 Societal context The acceptability and feasibility of screening for those who will be screened and those who will provide screening should be assessed. Whether screening is accepted depends on how the programme is designed and implemented. Acceptability is therefore difficult to predict from evidence for other sites or for other subgroups. The acceptability of screening may be assessed in advance by organizing focus groups of target populations, preferably with a risk profile and an age and sex distribution that matches that of the populations at highest risk. Consulting and working with affected communities and local civil society organizations that support them throughout the development and implementation of TB screening interventions will help to ensure that they meet the needs and expectations of communities and that they are accepted. Some people may accept screening more readily than others, depending on the perceived cost and inconvenience, as well as the adverse consequences of participating in screening or of a TB diagnosis (such as stigmatization or discrimination) as compared with the perceived benefits. TB screening is generally acceptable to most people (see more information in the Web Annexes B and C of the screening guidelines). Certain risk groups are more difficult to reach than others. T o some extent, the structure of health and social services determines which risk groups can be reached most easily. Generally, it is more feasible to conduct screening in well-defined risk groups that can be reached in a specific location, such as clinical risk groups within health facilities, people living in institutions (such as prisons) and people working in high-risk locations (such as mines). A screening intervention should not reduce health equity throughout the health services; therefore, any effort to screen hard-to-reach populations should be matched with appropriate resource mobilization. 2.2.3 Epidemiology of TB The main purpose of an epidemiological assessment is to identify gaps in TB case detection and opportunities for addressing those gaps through screening. The assessment should account for potential benefits, risks and costs of systematic screening, particularly in relation to other possible interventions. The analysis should be disaggregated by age, sex and geographical location, and special attention should be paid to vulnerable groups that are at high risk for exposure and/or progression to TB disease or are likely to face barriers to accessing TB services, or both. Systematic TB screening is", "recommended in geographical areas with an estimated TB prevalence of 0.5% or more. Such areas may be informal peri-urban settlements and slum areas, where entire neighbourhoods could harbour a large burden of TB. Epidemiological techniques like geographical information systems could be used to plot \u201chotspots\u201d for targeted action. Potential data sources include: \u2022 surveillance data (including laboratory data); \u2022 location of all TB diagnosis and treatment facilities, including in the public and the private sector; \u2022 data from TB prevalence and HIV incidence surveys; \u2022 evaluations of previous or continuing activities to improve case-finding, including screening; \u2022 national health and demographic statistics (including vital statistics and programmatic data); and \u2022 the findings of research.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 14 Box 1 lists WHO references on collecting data. \u00ce T uberculosis prevalence surveys: a handbook (15) \u00ce Understanding and using tuberculosis data (16) \u00ce Standards and benchmarks for tuberculosis surveillance and vital registration systems (17) \u00ce Framework for conducting reviews of tuberculosis programmes (18) \u00ce Public\u2013private mix for TB care and control: a tool for national situation assessment (19) \u00ce ENGAGE TB: integrating community-based tuberculosis activities into the work of nongovernmental and other civil society organizations. Operational guidance (20) \u00ce T uberculosis patient cost surveys: a handbook (21) \u00ce Contributing to health system strengthening \u2013 Guiding principles for national tuberculosis programmes (22) \u00ce Assessing tuberculosis under-reporting through inventory studies (23) \u00ce People-centred framework for tuberculosis programme planning and prioritization: user guide (24) Box 1. WHO sources of information on collecting and interpreting data 2.2.4 National TB programmes and the general health-care system High-quality services for TB diagnosis, treatment and management and support services for patients should be in place before or scaled up at the same time as systematic screening for TB disease. The availability of high-quality TB services will minimize the risk of negative effects of screening, including the risk of a false-positive result and the accompanying anxiety, the risk of a false-negative diagnostic test and unnecessary treatment and delay in receiving an appropriate diagnosis (especially if the quality of TB diagnostic services is suboptimal) or worsening of TB treatment outcomes if treatment services are suboptimal and not properly tailored to the vulnerable groups that may be targeted through screening. Moreover, systematic screening in the context of poor-quality general services raises ethical concerns and may reduce the confidence of the population in the services provided. In addition, the capacity of specific health institutions and health staff to take on additional functions related to TB screening should be carefully assessed to avoid undermining the quality of TB and other services. Where people would benefit from systematic screening for TB but high-quality services and health system capacity for TB diagnosis, treatment, management and support are not in place, the gaps should be identified and should serve as an impetus for investment to improve TB services and capacity in those areas. The critical conditions to be met or strengthened when implementing systematic screening are listed below. \u2022 Quality-assured diagnostic services are available, including specimen transport from the community to the nearest", "health facility for onward transport or to the nearest laboratory. The services should include the capacity to deal with anticipated increased demand in diagnostic testing. \u2022 Regular, reliable supplies of anti-TB medicines are available, and there is the capacity to treat the anticipated rise in cases of drug-susceptible as well as drug-resistant cases among adults and children.", "Chapter 2. The six steps in the planning and implementation cycle 15 \u2022 Regular, reliable supplies of TPT medicines are available, as those who are screened and do not have TB may be eligible for TPT . \u2022 There should be sufficient integration between TB and HIV services to ensure that all people with possible TB are tested for HIV . \u2022 The performance of TB diagnostic and treatment services must be considered acceptable by decision-makers, and processes should be in place to monitor and maintain quality. \u2022 There are sufficient mechanisms to provide social support for diagnosed patients, and there is capacity to tailor treatment programmes to the specific needs of the population to be screened. \u2022 If mWRDs are used to assess drug resistance, there is adequate capacity for further drug- susceptibility testing and for programmatic management of drug-resistant TB. \u2022 A mechanism should be in place to ensure that access to tests (mWRDs, radiography, other) for diagnostic purposes is appropriately prioritized in relation to tests for screening. \u2022 Adequate financial and human resources can be made available for screening without adversely affecting other key functions of the health-care system. 2.2.5 Health-care coverage and access to health services Before screening is started, it is essential to ensure that people with diagnosed TB have access to affordable, high-quality TB care. This may not be the case for certain vulnerable groups, such as migrants, refugees and homeless people, who may lack identity papers or health insurance. Inclusion criteria for screening, coverage of health insurance (where applicable) and access to health services should be assessed. The system should ensure that people do not pay out of pocket for screening and do not suffer financial hardship as a result of screening. 2.2.6 Protection from stigmatization, discrimination and harm Discrimination based on gender, sexuality, ethnicity or caste or against populations such as sex workers and people who use or inject drugs, can severely limit access to treatment, which may be reinforced by the lack of a framework for protecting human rights. The existing frameworks for protecting human rights and the extent to which they are enforced must be reviewed before systematic screening is implemented. Possible stigmatization of and discrimination against people screened for TB and people with diagnosed TB can create risks for people undergoing screening. For example, people with diagnosed TB may lose their jobs temporarily or permanently or be expelled from", "school or forced to divorce. The legal protection of the rights to care and to maintain employment must be considered. The legal status of migrants should be carefully considered when designing a screening plan, with regard to both their access to health services and their risk of expatriation if they are diagnosed with TB. If lack of protection of rights or other social risks affect people and communities that are at high risk of TB, measures must be taken to mitigate those risks as part of any systematic screening programme, and informed consent must be sought. While informed consent for TB screening is ethically required in all cases, it is especially important for populations who may face repercussions from a TB diagnosis. 2.3 Setting goals and specific objectives The primary goal of TB screening is to reach people who are not reached by the patient-initiated pathway and to detect TB disease early, thereby improving outcomes for individuals and reducing transmission and incidence at population level. Secondary goals of TB screening are to: \u2022 rule out TB disease in order to identify people who are eligible for TPT (4, 5); \u2022 identify people who are at particularly high risk of developing TB disease and thus may require repeated screening, such as people with an abnormal CXR (e.g. fibrotic lesion) that is compatible", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 16 with TB but who were not diagnosed with TB disease at the time of screening, people living with HIV , health-care workers and prisoners; and \u2022 better characterize TB risk factors by combining screening for TB with screening for TB risk factors (such as HIV , diabetes mellitus, chronic obstructive pulmonary disease, undernutrition or smoking) to map individual or community-level risk factors and socioeconomic determinants that should be addressed to prevent the disease more effectively. This may be an additional objective in settings where information about the prevalence and distribution of TB risk factors is lacking. Specific objectives can be based on those goals and according to a country\u2019s priorities and situation assessment. They may be based on specific targets or gaps identified in the situation assessment. The objectives should be specific, measurable, achievable, relevant and time-bound (SMART). 2.4 Identifying and prioritizing risk groups Risk groups include groups at high risk of exposure to TB or of progression to TB disease or who have limited access to TB services. The following risk groups should always be systematically screened for TB: \u2022 household and close contacts of people with TB, \u2022 people living with HIV , \u2022 people exposed to silica (mainly some miners) and \u2022 people in prisons and penitentiary institutions. For these four risk groups, the focus should be on how to screen and on the quality of screening, not if to screen. The assessment should include the size and distribution of the group, the TB burden in the group, past and current screening experience and any remaining considerations and challenges to be addressed to optimize screening. Other risk groups (T able 2.3) should be prioritized for screening according to local epidemiology and the goals and objectives of screening. Systematic screening for TB disease in children is challenging, as both the screening and the diagnostic tools are less accurate in children than in adults; therefore, there is a higher risk that large number of diagnostic tests will be required, with large numbers of false- positive cases that are unnecessarily started on TB treatment. In principle, only children who are close contacts of a person with TB and children living with HIV should be systematically screened for TB. Other children, including malnourished and internally displaced children, are to be assessed according to diagnostic algorithms for paediatric TB as part", "Chapter 2. The six steps in the planning and implementation cycle 17 Table 2.3 Additional risk groups to be considered for TB screening Potential site of screening Risk group Community Populations of geographical areas with a high prevalence of TB (estimated to be 0.5% or higher) Subpopulations with limited access to health care and with structural risk factors for TB, including those living in poor urban communities, homeless communities, communities in remote or isolated areas, indigenous or tribal communities or other vulnerable or marginalized groups with limited access to health care Outpatient and hospital inpatient departments and primary health-care centres People previously treated for or exposed to TB People with an untreated fibrotic lesion shown on CXR People with chronic respiratory disease People presenting with pneumonia People with diabetes mellitus People who smoke Undernourished people or people with a body mass index \u2264 18 People who have had a gastrectomy or jejuno-ileal bypass People with alcohol use disorder or drug use disorder People with chronic renal failure People on treatments that compromise their immune system Older people (60 years and older) Women who are pregnant (and up to 3 months postpartum) General outpatients and inpatients (in settings where the prevalence of both TB and of TB risk factors is high, it may be logistically more feasible to screen all health centre attendees) People in mental health clinics or institutions Residential institutions People living in shelters Other congregate institutions (such as the military) Immigrants from settings with a high prevalence of TB Immigration and refugee services People in refugee camps Internally displaced persons Migrant workers Workplaces with high occupational exposure People working in TB or veterinary medicine laboratories Prison guards and other workers in penitentiary facilities Other workplaces with a high prevalence of TB Health-care workers", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 18 Screening should be designed to reach the people at greatest risk of TB, including high-risk groups and communities with a high prevalence of TB; indiscriminate mass screening regardless of risk should be avoided. Risk groups should be prioritized for screening after assessment of the potential benefits and harm in relation to costs. Screening offers benefits for the individual (see 2.4.1) but may also be a risk and cause harm (see 2.4.2). The benefits of screening may also be seen at population level, as a reduction in prevalence and transmission (see 2.4.3). The balance between benefits and costs is further determined by the total potential yield (see 2.4.4), the NNS to detect a true case of TB (see 2.4.5), the feasibility of the initiative and the acceptability of screening to the group (see 2.2.2). Prioritization may also depend on which stakeholder is responsible for screening. For example, a national TB programme under the auspices of a ministry of health may have other mandates, priorities and resources than health services that are managed by a ministry of justice, ministry of labour, an immigration authority, a nongovernmental organization, a private health-care provider or an employer. A tool has been developed to assist in prioritizing risk groups for screening, which provides estimates of the potential yield of true- and false-positive TB results and the cost of screening, according to the risk group(s) targeted and the screening algorithm(s) used (see 3.3). 2.4.1 Potential benefits for the individual The benefits include the health, social and economic benefits of early diagnosis and treatment. In principle, the potential benefits are greater for persons who are at highest risk of delayed or missed diagnosis because they meet barriers in obtaining health care (for example, people living in poor communities or remote areas) and especially those at highest risk of unfavourable treatment outcomes when diagnosis is delayed (for example, because their immune system is compromised, such as people living with HIV and children). When someone is screened for TB, other conditions that require treatment may be identified (such as lung cancer or chronic obstructive pulmonary disease. Although the screening team may not be responsible for offering treatment for other conditions, links must be forged with other health programmes to address these cases. 2.4.2 Potential risks and harms for the individual The screening procedure itself may be inconvenient and have", "direct or indirect costs for the individual, which may vary with both the risk group and the screening approach. Harm associated with the results of screening include the unintended negative effects of a correct diagnosis (such as stigmatization or discrimination) and the harm caused by a false-positive or a false-negative screening test or diagnosis. Particular attention should be paid to harm to groups such as migrants, who may risk deportation if TB is diagnosed or presumed, and employees who lack legal protection against dismissal if they are diagnosed with TB. These risks should be identified, actively addressed and mitigated by the screening programme (see 2.2.6). The risk that screening leads to costs for the person being tested should also be reduced as much as possible, by ensuring that screening and potential further diagnostic testing and TB treatment is covered by insurance or the public health system. The risk of a false-positive screen or a false-positive diagnosis depends on the prevalence of TB in the screened group and on the screening and diagnostic algorithm used. The harm due to a false-positive screening test result includes stress, anxiety and further diagnostic workup. Harm due to false-positive diagnostic test result includes unnecessary treatment and events. Screening of groups with a low TB prevalence can result in a large proportion of false-positive results. Therefore, as a general rule, screening of low-risk groups should be avoided. The importance of choosing an appropriate screening and diagnostic algorithm to minimize the number of false-positive outcomes is further discussed in 2.5 and in Chapter 3.", "Chapter 2. The six steps in the planning and implementation cycle 19 Potential harm is often due to inappropriate implementation. Contextual considerations are therefore important to ensure that screening is well designed and implemented and that both the potential benefits and harm are considered throughout the screening and diagnostic pathway (25). 2.4.3 Potential impact on prevalence and transmission The potential of screening to affect transmission is theoretically highest in congregate settings, such as prisons or overcrowded urban slums, where there is a high rate of transmission and where there is also substantial in-migration and out-migration. In a study in Viet Nam, 3 years of community-wide screening decreased the prevalence of pulmonary TB (26). In principle, the larger the total yield of screening, the larger the potential impact on TB transmission in the community. However, when the TB burden is concentrated in a few high-risk groups, the largest impact on overall transmission will be generated by screening carefully selected groups, even if the overall impact may be relatively small. 2.4.4 Potential total yield of true TB cases Fig. 3 shows the potential yield of screening in a range of hypothetical risk groups with a range of relative risks of TB (assuming 100% coverage, acceptance of screening, sensitivity and specificity of screening). As illustrated in Fig. 2.2, the yield of TB screening in a specific risk group (in terms of the number of TB cases detected; y axis) depends on both the size of the risk group (i.e. the prevalence of the risk factor in the general population; x axis) and the relative risk of TB for that risk group (z axis). The yield is also affected by the acceptance of screening in the risk group (see 2.2.2) and the sensitivity of the approach (see Chapter 3). Fig. 2.2 Potential yield of screening as a function of the prevalence of the risk factor in the population and the relative risk of TB in the risk group (baseline incidence, 1000 cases in a population of 1 000 000) 0 500 1000 1500 2000 2500 3000 3500 4000 4500 Number of TB cases detected Prevalence of risk factor 0.10% 0.50% 1% 5% 10% 15% 20% 3 5 10 20 Prevalence of TB as a function of the prevalence of a risk factor and the increased risk for TB associated with the risk factor Relative risk of TB (risk ratio)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 20 Often, the groups at highest risk of TB are also the smallest, and groups with only a moderately elevated risk may be very large. For example, the population prevalence of HIV , which is associated with an increase in risk of up to 20 times, is usually less than 1% (except in some countries in sub- Saharan Africa), and the total number of close contacts of someone with TB (who also have a dramatically elevated TB risk) is usually a very small fraction of the total population. Nevertheless, risk factors such as having diabetes or undernutrition or living in a crowded slum, which usually pose moderate relative risks for TB (in the range of 2\u20133) could affect more than 10% of the total population. Therefore, screening the highest-risk groups often gives a low total yield in terms of the absolute number of TB cases detected. A high overall yield from screening may be possible only by achieving very high coverage of screening in large groups that have a moderate increase in the risk of TB; however, screening of these groups will generally require a higher NNS and might result in a higher cost per case detected than screening of groups at very high risk. The risk of a false-positive diagnosis is also higher in these groups. Therefore, there is often a difficult trade-off between the desire to achieve a large total yield and cost\u2013effectiveness. T able 2.4 shows the NNS for TB disease with different screening approaches by burden setting, as estimated from the studies reviewed for the latest guidelines on TB screening. Similar estimates for other risk groups are given in Web Annex C of the screening guidelines. Table 2.4 Number needed to screen (NNS) for TB disease in general populations and in community-based screening Primary screening strategy Weighted mean NNS (range) (number of studies) Low or moderate TB incidencea Medium or high TB incidencea Symptoms 4424 (2417\u20136031) n=1 1058 (31\u20134085) (n=22) CXR 3016 (n=1) 475 (186\u2013605) (n=3) Symptoms or CXR 1567 (23\u20132857) (n=3) 426 (125\u2013763)b (n=18) mWRD (Xpert MTB/RIF) \u2013 1002 (338\u20131010) (n=2) a Low or moderate TB incidence (up to 100/100 000 population), medium or high TB incidence (> 100/100 000 population) b 15 studies with 18 cohorts 2.4.5 Number needed to screen to detect a person with TB The NNS to identify one person with", "confirmed TB in a specific risk group is the inverse of the prevalence of detectable TB in that risk group , assuming 100% sensitivity of the screening and diagnostic tools being used. If a given risk group has a very low prevalence of detectable TB, many people will have to be screened in order to find one case of TB, and this will require a high NNS; however, if a given risk group has a high prevalence of TB that can be detected by the screening and diagnostic tools being used, fewer people will have to be screened for each case detected, resulting in a lower NNS. Fig. 2.3 illustrates the general concept of the NNS in a risk group.", "Chapter 2. The six steps in the planning and implementation cycle 21 Fig. 2.3 The number needed to screen (NNS) in order to diagnose one person with TB in any given risk group is roughly the inverse of the prevalence of the disease in that risk group low prevalence moderate prevalence high prevalence larger NNS moderate NNS smaller NNS NNS = Prevalence 1 At a prevalence of 200/100 000 population, the NNS is at least 500 (in practice, it will be higher when the accuracy of the screening is suboptimal). The prevalence of undetected TB in the general population is often less than 200/100 000, even in countries with a high burden of TB; therefore, screening the general population is not usually cost\u2013effective. The NNS is a rough indicator of cost\u2013effectiveness and of effort. Comparison of the NNS of risk groups provides a measure of relative cost\u2013effectiveness if it can be assumed that the cost of screening and treatment and the benefits of early treatment are the same for all risk groups. This assumption is, however, rarely valid in practice. For example, an NNS of 50 for contact investigation might mean that", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 22 a person visits 12 different houses over 2 days. In contrast, in another situation, an NNS of 150 might be found by verbal screening in a slum area where that many people can be verbally screened in 4 h. Clearly, the effort and cost of screening are higher in the first example, even though the NNS is lower. T o guide prioritization of risk groups, the NNS should be estimated, even approximately, for each group being considered for screening, and it should be specific to the screening algorithms being used. This process is described in detail in Chapter 3. 2.4.6 Cost\u2013effectiveness and cost\u2013benefit analyses Before implementation of a programme, its cost\u2013effectiveness, or cost-benefit \u2013 in which costs and benefits are compared in monetary terms \u2013 can be modelled from estimates of the predicted number of additional true-positive TB patients detected, the reduction in morbidity, the reduction in the time that a person remains infectious and reductions in transmission, incidence and mortality. Cost will depend on the NNS, the algorithm used for screening and diagnosis, the method used to reach people for screening and the direct and indirect costs incurred by the screened individuals. Models can be used to estimate how costs are related to the potential impact on TB transmission and epidemiology. Some empirical evidence on the impact of active community-wide screening on the prevalence of tuberculosis is beginning to emerge (26). The ScreenTB tool can be used as a basic calculator of cost per case detected through screening (see 3.3). 2.5 Choosing algorithms for screening and diagnosis Screening algorithms combine one or several screening tests and one or several diagnostic tests. The accuracy of different screening tests and potential algorithms for different populations and the considerations to be made when selecting algorithms, are discussed in detail in Chapter 3. 2.6 Planning, budgeting and implementing 2.6.1 Requirements for planning, human resources, commodities and budgeting Consideration should be given to the extra resources, both human and financial, that will be necessary to prepare for, carry out and monitor screening activities and to accommodate the increased demand for testing of people with presumptive TB and the extra patients who may be identified by screening. T o determine which cadre(s) of staff should be involved in screening, current terms of reference, workload and the capacity of different staff should be reviewed, including", "supervisory staff and staff that provide commodities (e.g. equipment, software, consumables) for front-line screening workers. Programmatic experience in screening within health facilities and during outreach might provide lessons. There may be opportunities for task-sharing and task-shifting by involving communities (leaders, volunteers, ex-TB patients, civil society agencies, religious groups) and people in the target populations who may be trained in mobilization or even in some of the screening activities. The model of staffing and supervision may be highly context-specific (even within countries) and might vary between urban and rural settings and targeted risk groups. New data collection systems, preferably electronic, may be required, and training will be necessary. Screening can be done by a variety of personnel, depending on the tests being used. For instance, symptom screening can be conducted by community health workers or volunteers. New diagnostic equipment or additional tests may be required for additional activities. In many cases, the logistics of gaining access to and testing the target population will also require significant resources. If one of", "Chapter 2. The six steps in the planning and implementation cycle 23 the goals of screening is to increase the number of people beginning treatment, it will be important to ensure that there is an adequate supply of medicines for treating TB disease and for prevention; it will also be important to ensure that patients receive adequate support during treatment. 2.6.2 Choosing a screening programme model The choice of screening programme will have implications for the resources required and the potential reach and effectiveness of the programme. The decision on which model to use should be based on determining which approach will be most effective for reaching the targeted risk group with the resources available. The effort and resources required to reach the target population can be limited by screening in locations where people gather for other purposes, such as health centres or workplaces, although not all populations can be reached in this way. Programmes that bring screening to places where people live or work can reach more vulnerable populations, particularly those for whom there are barriers to accessing care, but these programmes require more resources. Such programme models can include continuous community-based case finding or periodic event-based case-finding (27). Examples include home visits, mobile outreach screening campaigns, community-based screening events with or without door-to-door mobilization, such as health fairs, and differentiated service delivery events, such as ART adherence meetings. Fig. 2.4 shows different forms of screening programme models. Fig. 2.4 Screening programme models Screening health centre attendees Occupational screening or screening in prisons or places hosting refugees Screening in the home Mobile outreach screening campaign Community-based screening events (health fairs)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 24 2.6.3 Ethical considerations Ethical issues should be considered from the onset of planning and should involve end-users. The design of screening interventions for specific risk groups should involve risk groups and organizations that might work with these populations, especially groups that face specific access barriers or discrimination. This should help in arriving at user-friendly, acceptable, effective approaches and building demand for services and their use. Those invited for screening should be provided with detailed information, including the benefits and risks, and verbal informed consent should be obtained. Refusal of screening should be respected and should not lead to discrimination of any sort. Informed consent requires effective communication with each person about the uncertainties associated with screening, such as false-positive results and risk of overtreatment. Appropriate mechanisms for obtaining informed consent should comply with international human rights standards and account for different languages, literacy and legal status. Risk and uncertainty must be communicated in a way that is culturally and linguistically appropriate, including to people whose first language is foreign to the local setting, to children and to people in prison. Confirmatory tests should be available to ensure an effective diagnostic pathway. The privacy and confidentiality of all information related to screening should be ensured. The risks of discrimination and stigmatization should be carefully assessed before initiating screening. Depending on the risks identified for different target groups, measures may be adapted to minimize the consequences. Further information on ethical considerations can be found in the WHO Ethics guidance for the implementation of the TB strategy (28). 2.6.4 Involving stakeholders and partner organizations and establishing roles Many different stakeholders and partners may be involved in screening for TB. It is important to involve communities and the target population when planning activities to ensure that the screening activities are feasible and acceptable. These stakeholders may also be able to plan mobilization and sensitization to inform the target population and motivate them to be screened. The programmes, services and stakeholders identified for collaboration in screening (see 2.2.1) should collaborate in the planning of screening. Planning for the required financial and human resources should account for all possible stakeholders who may be involved. Similarly, planning should include stakeholders who may be involved in developing supply chains for tests and equipment, as well as referral chains to ensure that those who are found to have", "TB receive appropriate care. Good coordination among stakeholders is necessary to ensure complementarity and to avoid overlap or conflicting approaches. 2.6.5 Mobilizing resources The goal of resource mobilization is to support the start-up, pilot-testing and maintenance of TB screening. In the initial phases, national TB programmes may not have allocated funding for new screening activities, and funds might have to be sought from alternative domestic and external sources (14). Usually, once screening activities become routine and are shown to be effective, funding becomes available from mainstream domestic and external TB programme budgets. In the medium to long term, as the TB epidemic is better controlled, TB prevalence decreases and the NNS increases, and resource mobilization may have to shift to maintaining funding levels to find fewer and fewer people with TB. Once the TB epidemic reaches near-elimination, national TB programme budgets may be expected to be reduced while still maintain high-quality screening among at-risk groups.", "Chapter 2. The six steps in the planning and implementation cycle 25 2.6.6 Pilot-testing It is critical to pilot-test a newly designed screening programme to ensure that it is operational. Pilot- testing is a valuable opportunity to refine new instruments (e.g. digital radiography, CAD and CRP), protocols, data systems and management structures. It also allows initial evaluation of the performance of the screening programme in terms of yield and costs to ensure that it has the intended effects on case detection, so that the design or the protocol can be modified if necessary. 2.7 Monitoring, evaluating and modifying the programme A monitoring and evaluation plan should be part of any screening programme. General conditions and risk group-specific conditions for discontinuing screening should be established from the outset \u2013 for example, in relation to yield, contribution to overall case detection and improvement in treatment enrolment and outcomes, cost per case detected or some combination of these. Indicators should be chosen, and digital forms created for collecting data or adapted to the specific objectives and local conditions. T o monitor yield and the NNS in each targeted risk group, an appropriate information system should be developed to generate data about the number of people diagnosed with TB in relation to the number of people approached, screened and tested. This information should be assessed periodically and the mix of approaches adjusted appropriately. The general epidemiology of TB, the importance of different risk groups and the epidemiology of TB in each group may change over time, and prioritization for screening will have to be adapted accordingly. As some members of a particular risk population will eventually find their way to diagnosis through the patient-initiated pathway if they are not screened, it is of interest to evaluate the impact of screening a particular group on overall additional notifications in a larger basic management unit or group of basic management units. This will require analysis of notification trends, preferably with comparisons to control areas. It is also important to measure whether screening is simply concentrating case-finding in a few facilities, which may be the case if a specific intervention is seen as beneficial and information about it spreads through the community. This can result in increased notification in one area and decreased notification in another. As one objective of screening is early detection, it may be useful to measure delays in diagnosis and treatment, which will", "require special surveys. T reatment outcomes and mortality rates among detected TB patients can, however, be captured and evaluated more easily. 2.7.1 Developing a plan for monitoring and evaluation Monitoring and evaluating systematic screening should be incorporated into the monitoring and evaluation programmes used in the national TB programme. The programme will determine the roles of the people involved in monitoring and its characteristics (e.g. frequency of monitoring, methods used, how the information collected will be fed back to adjust screening). T argets should be set for the expected caseload and yield, the NNS and costs in relation to benefits. T argets should be based on the estimated under-detection in different settings but should also account for programme realities. Screening interventions that are expected to require additional funding and resource mobilization should be appropriate to the need. 2.7.2 Proposed indicators Approaches to screening will depend on each group, and intervention-specific indicators should be developed for each approach. In general, however, the data on indicators shown in Fig. 2.5 should", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 26 be collected for each targeted risk group, such as all close contacts of TB patients or all people living with HIV in care. Fig. 2.5 Data to be collected for systematic screening programmes for TB Number of people successfully completing TB treatment Number of people screened for TB Number of people with presumptive TB identified Number of people evaluated for TB disease Number of people diagnosed with TB Number of people initiated on TB treatment Number of people eligible for TB screeningA B C D E F G The data collected can be used to calculate the following basic indicators for each risk group: \u2022 acceptability: the proportion of people screened for TB among those eligible (B/A); \u2022 screened positive: the proportion of people presumed to have TB among those screened (C/B); \u2022 testing retention: the proportion of people tested or evaluated for TB with a confirmatory diagnostic test among patients presumed to have TB (D/C); \u2022 NNS and number necessary to treat: the proportion of people diagnosed with TB among those screened (E/B) and tested (E/D); \u2022 linkage to care: the proportion initiating TB treatment among those diagnosed (F/E); and \u2022 treatment success: the proportion of people who successfully complete TB treatment among those who initiated treatment (G/F). It is critical to monitor the yield of bacteriologically confirmed and unconfirmed TB patients. A high proportion of unconfirmed TB patients referred from screening programmes might indicate over- diagnosis and should lead to closer evaluation of screening and diagnostic routines, considering the limitations of the diagnostic tests and the need for empirical or clinical diagnosis for certain populations, such as people living with HIV and children. In the case of late-stage detection of TB patients, the proportion of people with presumptive TB among those screened (C/B) and the proportion of those diagnosed among those screened (E/B) would be high. This finding would suggest a need for wider active TB case finding in a risk group. Low values for indicators such as the proportion of eligible people screened (B/A), the proportion of those tested who receive diagnostic confirmation (D/C) and the proportion of people diagnosed who start treatment (G/F) may reveal weaknesses in capacity at critical points in the TB care pathway, which should be addressed. Data should be disaggregated by variables such as age group and sex. This requires collection", "Chapter 2. The six steps in the planning and implementation cycle 27 Additional indicators of process (such as the number of people reached and screened per day, the time required for each step of screening and diagnosis and the number of people who require referral) should be collected during the pilot phase of a screening programme to ensure that it operates as designed and to inform logistics and capacity (e.g. number of tests needed). These data are easier to collect precisely than estimates of eligible populations and may indicate problems and can help to plan operational capacity (e.g. screening activities via mobile-vans over time). Once the programme has been established, however, these additional indicators should be discarded and the focus be shifted to streamlining the programme and scaling it up. The uptake of screening in a risk group (that is, the proportion of those eligible for screening who are actually screened) can be assessed only if the size of the target group has been well defined. It is usually possible to obtain the relevant information for screening conducted in health facilities, closed settings (such as prisons) and through contact investigations; however, it is often difficult to obtain such information in outreach screening programmes, such as when screening is done in the community, although the estimated population of a targeted community provides a rough estimate of the eligible population. Whenever screening is done, a baseline TB notification rate should be set from historical data, if available (29). These data are usually available to most programmes from notification records. If they are stored in case-based format (or individual patient data), they will permit more extensive disaggregation by the risk groups of interest. Historical data may have to be adjusted for time trends. Screening may generate a substantial yield but with no real change in TB notifications. This could indicate badly located screening points, but may also be the product of better case finding in populations that were previously neglected and a decrease in false-positive cases that previously inflated notification numbers. If this is the case, the proportion of notified TB patients with bacteriologically confirmed disease would be expected to increase over time even if the numbers remain stable. 2.7.3 Routines for recording and reporting T o obtain the information required for the indicators described above, a recording and reporting system for TB screening should include the following elements. \u2022 A log of", "the number of people screened in each risk group. A special database with information for each person screened may be used to obtain more refined data on subcategories of people within a risk group. Collection of these data is resource-intensive, but it may be relevant when a screening programme is started as part of an operational research project. Electronic data collection facilitates the process and permits easy transfer of information. It may be feasible to collect this type of data continually for certain risk groups, such as people seeking care in medical facilities. \u2022 A database of all individuals presumed to have TB who underwent further diagnostic evaluation. If a database is used to collect individual-level information for all people who are screened, this information can be included by adding a variable. \u2022 Additional variables in the digital laboratory register to indicate whether the tested patient was identified through screening, which screening methods were used to identify the patient and to which risk group the patient belongs. \u2022 Additional variables in the treatment register to indicate whether the patient was identified through screening and to which risk group the patient belongs. \u2022 Other forms or databases may be necessary, depending on the approach used and the existing databases or registers. For example, if contact investigation is implemented, there should be specific data-capture tools to track this activity properly. Such tools can be used on smartphones or other mobile devices at the site of investigation.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 28 2.7.4 Programmatic evaluations Depending on the objectives of the screening programme and the results of monitoring the indicators discussed above, a special assessment may be necessary to determine, for example, the reasons for low uptake of screening, an unexpectedly low proportion of people presumed to have TB identified by screening, a low proportion of those presumed to have TB who were further evaluated for TB, a higher-than-expected NNS or a high proportion of cases that are not bacteriologically confirmed. Programmes are unlikely to be able to replicate the performance observed in trials and other studies conducted under controlled conditions, in which study subjects may even have been pre-screened. Additional quantitative and qualitative analyses may be necessary to determine whether there are barriers to screening, to identify opportunities to improve the screening approach and whether there have been any social or financial consequences of screening (e.g. costs of CXR and travel shifted to patients). It is also prudent to evaluate the effects of screening on overall operations at health clinics, especially the impact of an increased burden of laboratory testing. 2.7.5 Monitoring time trends for re-screening and re-prioritization A successful screening programme may lead to a diminishing yield over time, at least if the risk group is a fixed population. Over time, changes in the background burden of TB and changes in the profile of TB patients in the community (for example, a trend towards fewer patients with symptomatic TB, fewer cases of sputum smear-positive TB and decreasing TB mortality) can lead to a reduction in the yield from screening, an increase in the NNS, a reduction in cost\u2013effectiveness and a change in the ratio of benefits to harm. Successful programmes that facilitate access to care may also lead to diagnosis of more people with TB through screening than via the patient-initiated pathway. T rends in all these indicators should be monitored, and the priority of risk groups, the choice of screening approach and the screening interval should be reassessed regularly. Criteria for stopping screening should be established before a screening initiative is implemented.", "Chapter 3. Screening tools and algorithms 29 Chapter 3. Screening tools and algorithms The algorithms for screening in the general population and in high-risk groups (not including people living with HIV) are presented in Fig. A1.1 - A.1.10 in Annex 1 . 3.1 Screening tools Screening tests should distinguish between people with a high likelihood of having TB disease from those who are unlikely to have TB. A screening test is not intended to be diagnostic but rather to identify the subgroup of people with the highest likelihood of disease. Screening must always be conducted with a screening and diagnostic algorithm; thus, if people screen positive, they are referred to the next step in the algorithm, which could be a subsequent screening tool or diagnostic evaluation with bacteriological testing to confirm or rule out TB disease. In general, high sensitivity is important for screening tests, as the goal is to detect TB disease early, although, if specificity is low at the screening stage, a significant proportion of people being screened who do not have TB disease will be referred for additional screening or diagnostic evaluation, with additional costs. Thus, the objectives of the screening programme must be considered when selecting a screening and diagnostic algorithm, including maximizing case detection (and thus prioritizing sensitivity) or maximizing efficiency (and thus prioritizing specificity). See 3.2 for further discussion of screening and diagnostic algorithms. The tools for initial screening of the general population and high-risk groups (not including people living with HIV) include symptom screening for clinical features associated with pulmonary TB (including cough, haemoptysis, weight loss, fever or night sweats) and screening with CXR or an mWRD. T able 3.1 presents the accuracy of these tools observed in studies of populations without HIV , from a systematic review presented in 2020 as part of the update of the TB screening guidelines, with bacteriologically confirmed TB as the reference standard (30) (see Annex 2 for more details). It should be noted that most data on the accuracy of screening tools derives from TB prevalence surveys, in which screening for TB is conducted in the general population in high-burden settings. Thus, their performance in other populations and settings may differ; particularly in clinical settings, generally with a sicker population, the tools may not perform as well. Screening tools and algorithms for people living with HIV are discussed in Chapter 5, and those for children in", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 30 Table 3.1 Diagnostic accuracy of symptoms, CXR and mWRDs for screening for TB disease among HIV-negative individuals * Screening test Sensitivity (%) Specificity (%) Prolonged cough (\u2265 2 weeks) 42 94 Any cough 51 88 Any TB symptom (cough, haemoptysis, fever, night sweats, weight loss) 71 64 CXR (any abnormality) 94 89 CXR (abnormality suggestive of TB) 85 96 MWRDs (adults at high risk) 69 99 * For people living with HIV , see Chapter 5. For more detail on the systematic review and data presented here, see Web Annex B of the guidelines) 3.1.1 Symptom screening Symptom screening is feasible, easy to implement and low-cost. It is also highly acceptable, because it is non-invasive and is a usual part of the clinical assessment of people under care. Symptom screening, particularly for cough, has the added advantage that it usually detects people with TB who are most likely to transmit the disease. Symptom screening has, however, low and variable sensitivity especially for detecting TB early. The positivity rate for screening with symptoms differs from setting to setting, depending on the prevalence of other, non-TB conditions and the quality of screening. In particular, the occurrence of cough may vary with the frequency of other lung conditions, smoking and levels of air pollution. Symptom screening is also subjective and depends on the interpretation of the provider conducting the screen and the person being screened. For example, definitions of cough may differ (e.g. any cough, current cough, \u201clong-standing\u201d or prolonged cough, cough lasting \u2265 2 weeks). Cough The review performed for the 2021 guidelines update estimates the sensitivity of screening for any cough for detection of TB disease is 51%, which implies that, in many settings, about half of people with TB do not cough; therefore, screening for this clinical feature alone would detect only about half of people with TB disease. In contrast, it has a fairly high specificity (88%), suggesting that, in many settings included in the reviews, most people without TB disease did not cough. This is likely to depend on the prevalence of non-TB diseases and other conditions in the population being screened. Screening for prolonged cough \u2013 defined as lasting \u2265 2 weeks \u2013 is estimated to be even less sensitive (42%) but highly specific (94%) ( T able 3.1). It can be a helpful screening tool", "for programmes that wish to be efficient and reduce the number of people without TB referred unnecessarily for diagnostic testing, but it will not detect the majority of people with prevalent TB, which is unacceptable for most screening interventions. ? Prolonged Cough FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms #29", "Chapter 3. Screening tools and algorithms 31 Any TB symptom An alternative is to screen for any symptom that commonly occurs in TB, including cough of any duration, sputum, haemoptysis, fever, night sweats and weight loss. In studies reviewed for the latest revision of the screening guidelines, the estimated sensitivity of screening for any TB symptom is 71% \u2013 higher than for cough alone but with lower estimated specificity (64%) ( T able 3.1). The positivity rate can be quite high in certain populations, as the same symptoms may be caused by other conditions. In contrast to cough alone, the lower specificity of any symptom would imply that more people without TB would be sent for diagnostic evaluation and more tests would have to be done to confirm one TB case. 3.1.2 CXR screening CXR is a rapid imaging technique for identifying lung abnormalities. It is used in clinical evaluation for conditions of the thoracic cavity, including the airways, ribs, lungs, heart and diaphragm. CXR is a good screening tool for pulmonary TB because of its high estimated accuracy for detecting TB disease, especially before the onset of symptoms. From the perspective of the person being screened, CXR is valuable because it can also detect medical conditions other than TB, including other pulmonary and thoracic conditions. The sensitivity of CXR for the threshold of any abnormality is estimated to be 94%, and its specificity is estimated to be 89% (T able 3.1). For a threshold of an abnormality suggestive of TB, the estimated sensitivity is lower (85%) but the specificity is higher (96%). Thus, either \u201cany abnormality\u201d or \u201cabnormality suggestive of TB\u201d detected by CXR can be used, depending on the context, radiological expertise, the availability of other resources, including diagnostic testing, and a preference for higher sensitivity or for higher specificity of the screening algorithm. Although CXR is the preferred screening tool from the viewpoint of test accuracy, it can be expensive and logistically challenging to use, especially during active case finding, when screening is done as an outreach activity outside the health services. It is important to keep in mind that people may have to travel away from their usual facility for a CXR and to pay for it out of pocket. CXR is a good choice in most screening scenarios, particularly those based in a healthcare setting or where mobile X-ray technology can be used, but it", "is not feasible in some scenarios. Implementation considerations for CXR as a screening tool Equipment and resources \u2022 Implementation of CXR requires equipment. Consider the resources required (budget, health workforce, personal protective equipment, imaging equipment). \u2022 Ensure the functioning of radiography equipment and establish a mechanism for regular maintenance for optimal functioning of the equipment. \u2022 Portable chest radiography equipment can increase access to TB screening for eligible populations outside the health centre (31). Digital technology \u2022 Favour digital radiography equipment to increase access to CXR screening, as the throughput can be higher and the time for processing shorter and it will reduce the environmental impact of used films and printing. Newer radiography technology emits lower doses of radiation and may be much more portable (31). TB Symptoms ? FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms #30 CXR ? FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms #31", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 32 \u2022 Comparison of multiple CXR images for the same individual over time can aid diagnosis. If appropriate technology and processes are available, archiving and retrieval of digital images may be more convenient than for physical films. \u2022 Consider the transfer of images for remote reporting (teleradiology) and CAD of TB on digital radiographs as necessary to broaden implementation of CXR for screening (e.g. in settings where radiologists are not available for on-site reporting, or their availability is scarce). Skilled CXR reading and interpretation and appropriate follow-up \u2022 Provide appropriate training of radiologists and technologists to maximize the accuracy of reading of images by accepted local protocols. \u2022 Develop standard operating procedures for use of CXR and for appropriate follow-up, including for abnormalities associated with diseases other than TB. \u2022 Develop job aids to assist providers in informing the test recipient and to respond to frequently asked questions about the utility and procedure of CXR. \u2022 Strengthen mechanisms for supportive supervision and monitoring of accurate implementation. \u2022 Develop tools for systematic recording and reporting of CXR findings and linkage to confirmatory diagnostic testing. Access \u2022 Consider providing funding for people to travel for CXR screening or using mobile screening to improve access to CXR screening (32). \u2022 Patients should not have to make out-of-pocket payments for CXRs performed as part of TB screening. Consider removing patient costs for CXR entirely or using vouchers to further reduce barriers to accessing this critical tool for TB control. Safety of radiation \u2022 Radiography involves exposure to some ionizing radiation, which may increase the long-term risk for cancer. Recent innovations in radiography have substantially reduced exposure to radiation. CXR is largely considered safe at a radiation dose of 0.1 mSv, which corresponds to 1/30 of the average annual radiation dose from the environment (3 mSv) and 1/10 of the annual accepted dose of ionizing radiation for the general public (1 mSv). Manufacturers provide information on doses in technical specifications of the machine being used. \u2022 When performing CXR, minimize the radiation dose while maintaining diagnostic image quality (e.g. low-dose scanning protocols); use digital imaging rather than film-screen equipment. \u2022 Lead shields can be used to reduce exposure to ionizing radiation of other parts of the body. While lead shields are preferred, they are not a requirement for conducting CXR as part of TB screening,", "and exposure to ionizing radiation can be minimized in other ways. \u2022 Pregnant women are especially vulnerable to ionizing radiation from radiography. CXR does not pose any significant risk for pregnant women or the fetus, provided that good practices are observed, with the primary beam targeted away from the pelvis. Children have a longer life expectancy and therefore more time to develop radiation-induced health effects within their lifetime. \u2022 Inform the person who is screened about the safety provisions for radiation protection. For more resources on use of CXR for TB screening \u2022 WHO Chest radiography in TB detection: https://apps.who.int/iris/handle/10665/252424 (33) \u2022 TB prevalence surveys: a handbook: https://www.who.int/tb/advisory_bodies/impact_measurement_ taskforce/resources_documents/thelimebook/en/ (35)", "Chapter 3. Screening tools and algorithms 33 3.1.3 CAD technologies for screening and triage CAD software packages have been introduced to automate interpretation of digital CXR images for pulmonary TB disease- related abnormalities. CAD products analyse digital CXR images and generate a continuous numerical score that corresponds to an increasing likelihood of TB as the score increases. It should be noted that the scores are usually between 0 and 1 or 1 and 100 but are not percentages, and they should not be interpreted as directly reflecting the risk of TB. CAD can resolve numerous difficulties in human interpretation of CXR. These include the lack or scarcity of trained health personnel to interpret radiographic images for TB screening and substantial intra- and inter-reader variation in correct detection of abnormalities associated with TB. CAD could thus allow significant scale-up of TB screening and increase access to CXR screening. The score given by CAD when reading a chest film relates solely to the likelihood of TB; in contrast a human reader can identify between multiple pathologies simultaneously when interpreting a CXR. The performance of three CAD software programmes \u2013 all of which were on the market by January 2020 and had received a CE mark1 \u2013 were evaluated for the update of the TB screening guidelines. The performance of the class of software was assessed in multiple external evaluations against a library of digital radiographs and associated clinical data, independently of validation studies conducted by the product manufacturers themselves. These evaluations indicated that CAD software programmes are accurate and their performance compares well with human interpretation of CXR for detection of pulmonary TB disease. The recommendation that CAD software programmes be used in place of human readers for interpretation of digital CXR in screening and triage for TB disease applies to software brands that are found by external evaluation to have a performance that is not inferior to that of the products reviewed by the Guidelines Development Group in 2020. It should also be noted that the recommendation is specific to adults and adolescents aged 15 years and older and applies only to interpretation of antero-posterior or postero-anterior views of digital plain CXR for pulmonary TB. If a programme includes use of CAD for automated interpretation of CXRs as part of screening or triage, it is essential that calibration be conducted to determine the appropriate threshold score for any given setting and", "programme according to the spectrum of radiographic findings in members of the target population with and without TB disease. Section 4 describes a toolkit for implementation and calibration of CAD technology for screening and triage, including a protocol and guidance for conducting a CAD calibration study and a web-based tool to facilitate analysis of data, calculation of receiver operator characteristics (ROC) curves, the accuracy of different thresholds and interpretation of findings. Considerations for implementing CAD technology for screening or triage \u2022 Implementation of CAD will require thorough consideration of the infrastructure requirements, including digital radiography equipment, electricity, computer availability, Internet access, and the fees for use and the cost of the licence for the CAD products. The resources required and cost\u2013 effectiveness will depend on the setting, including the current availability and salaries of human readers. \u2022 Although CAD technologies can reduce the burden on human readers, maintenance of human reader capacity for TB screening radiography is essential, for example for children aged < 15 years for whom CAD is not currently recommended or for interpretation of abnormal images when a disease other than TB is suspected. 1 CAD4TB v6, from Delft Imaging; Lunit Insight CXR, from Lunit Insight; and qXR v2, from Qure.ai ?", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 34 \u2022 The abnormality score thresholds recommended by the manufacturer, when available, do not perform uniformly in different contexts. Users may also differ in their preferences for higher sensitivity or specificity, depending on their circumstances or objectives of screening (e.g. desire to maximize case detection rather than reduce false-positive screening test results). CAD software should thus be calibrated for each setting or population in which it will be used for screening. \u2022 After initial calibration, monitoring and analysis of CAD performance should continue. This may include assessment of consistency with human reader interpretation, proportion of images read as abnormal and requiring further investigation and the proportion of patients with images read as abnormal who have bacteriologically confirmed TB. 3.1.4 Molecular WHO-recommended rapid diagnostics for screening mWRD are rapid, sensitive molecular tests for detecting TB. In the 2021 update of the screening guidelines, mWRDs are also recommended for screening for TB disease. 2 For the purposes of this handbook, the mWRDs that can be used for screening are Xpert\u00ae MTB/RIF and Xpert MTB/RIF Ultra (Cepheid, USA), loop-mediated isothermal amplification (LAMP , Eiken Chemical, Japan) and T ruenat\u2122 MTB and MTB Plus tests (Molbio Diagnostics, India). Several considerations apply to use of mWRDs as a screening tool. mWRDs perform differently when used for screening than when used for diagnosis. The sensitivity of mWRDs for screening high-risk populations (non-HIV-infected) is estimated to be 69% and the specificity 99% (see WHO consolidated guidelines on TB diagnosis for estimates of mWRDs used for diagnosis (12)). Because of the differences in accuracy and the lower TB prevalence typically found in a population undergoing screening rather than diagnostic evaluation, the positive and negative predictive values of mWRD also differ. For example, despite a quite high estimated specificity of 99%, over one half of positive screening tests will be false-positive when mWRDs are used to screen a population with a 1% prevalence of TB. Thus, the different implications for clinical interpretation and programmatic use of mWRDS for screening and for diagnosis must be understood. People who screen positive for TB with an mWRD should always be followed up with a thorough clinical evaluation, including symptom screening and further tests, such as CXR or repeat mWRDs on additional sputum samples, to establish a definitive diagnosis of TB. For patients with a history of TB in the previous 5 years,", "a positive result may be due to the detection of DNA persisting from the earlier TB episode. Therefore, a positive test in such cases should be investigated with phenotypic methods to exclude a false-positive result (12). A negative mWRD for a single sputum sample does not exclude TB, as patients with TB may test mWRD-negative because they cannot produce sputum or an adequate quantity of sputum, have a very low bacillary burden in the sample or have extrapulmonary disease. Considerations for using mWRDs for screening With use of mWRDS for screening, test results are in theory available within a few hours; however, because of laboratory batching and burden, they are usually available within 1-2 days. Inefficient reporting (on paper forms) and transport of samples introduce additional delays. A delay of more than a few hours could adversely impact the retention of patients in the screening pathway and should be considered before use of mWRDs for screening. Implementation of mWRD as a screening tool will require significant resources, including increased capacity and expansion of diagnostic and sample transport networks. There has been limited experience in widescale use of mWRDs for screening under programmatic conditions. Priority should be given to ensuring universal access to mWRDs as a diagnostic test for TB and drug-resistant TB before extending its use to screening. If use of mWRDs for screening requires decentralization of the 2 In the reviews conducted to update the TB screening guidelines, the only data for evaluation of mWRDs for screening pertained to Xpert MTB/RIF mWRD ? FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms #33", "Chapter 3. Screening tools and algorithms 35 technology, there may be significant implications in terms of the purchase of machines, cartridges and other consumables, an uninterrupted supply of electric power and maintenance. If mWRD does not reach most health centres, samples will have to be transferred; in this situation, shifting from mWRDs for diagnosis to screening would substantially increase the workload for sample transport. Diagnostic connectivity platforms that automate the transmission, storage and retrieval of test results will improve the utility of mWRDs for decision-making. 3.1.5 Tests of TB infection The tuberculin skin test, like the Mantoux test and interferon-g release assays should not be used in screening of TB disease (13, 34). These tests cannot distinguish TB infection from TB disease and cannot predict who will progress to TB disease. The role of these tests in decision-making for TPT is discussed elsewhere (4). 3.2 Algorithms for screening 3.2.1 Basic features of TB screening and diagnostic algorithms An algorithm for systematic TB screening should combine one or several screening tests and a separate diagnostic evaluation for TB disease, as recommended by WHO (12). A negative diagnostic test result may be followed up by further clinical evaluation if clinical suspicion of TB is still high. This could include re-testing with the same or another diagnostic method and/or close follow-up of clinical symptoms with or without chest imaging. A positive diagnostic test result might have to be re-confirmed with further testing and clinical evaluation if the positive predictive value of the test result is low. Different configurations of screening tests have different implications for the sensitivity, specificity and costs of the algorithm. Single screening algorithms comprise one screening test; people who screen positive require diagnostic evaluation for TB. Examples of single screening algorithms are screening all clinic attendees for any cough or a mobile van screening campaign in which everyone in the community is screened by CXR. Parallel screening algorithms comprise an initial screening step with two screening tests (e.g. screening for symptoms and CXR simultaneously). A positive or abnormal result in either (or both) screening test is an indication for referral onwards towards a diagnostic evaluation. Parallel screening algorithms are more sensitive, as they capture a broader population of people to be evaluated for TB with a diagnostic test. This approach is ideal if the goals of screening are to maximize case detection or to measure the prevalence of TB in", "the population being screened. (A parallel screening approach is used in prevalence surveys, in which screening for symptoms is combined with CXR) (15). Parallel screening algorithms are, however, typically less specific and therefore have higher cost implications because of the larger number of people referred for diagnostic evaluation and a higher risk of false- positive screening results. Serial screening algorithms comprise two screening tests conducted successively, with referral for a second screening test according to the results of the first test. A sequential positive serial screening algorithm is one in which a positive or abnormal result on the first test requires referral to a second screening test, followed by diagnostic evaluation of those who screen positive on both screening tests. An example of this approach is screening for any TB symptom, followed by screening by CXR for those with symptoms. This screening approach increases the pre-test probability of TB in the population being screened before referral for diagnostic evaluation, thereby increasing the efficiency of the screening programme and reducing the risk of false-positive diagnoses. This approach is, however, less sensitive.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 36 A sequential negative serial screening algorithm is one in which a positive or abnormal result on the first screening test results in referral to diagnostic evaluation, while a negative or normal result on the first screening test results in referral for a second screening test and then subsequent referral for diagnostic evaluation for those who screen positive or abnormal in the second screening test. A sequential negative serial screening algorithm has the same sensitivity and specificity as a parallel screening algorithm with the same tests (the same number of people will be referred for diagnostic evaluation) but reduces the cost, because the second screening test is limited to individuals who test negative in the first. For example, an algorithm that begins with screening for symptoms and then CXR for those who do not present with symptoms will result in fewer CXRs being conducted with the same case detection as CXR plus symptom screening for all. This may, however, introduce delays, given that the tests are not run simultaneously. The specificity of a negative sequential screening approach will be lower than that of a positive sequential algorithm because of the larger number of people referred for diagnostic evaluation and the higher risk of false-positive screening results. 3.2.2 Screening and diagnostic algorithm options This operational handbook includes 10 screening algorithm options for screening the general population and groups at higher risk (not including people living with HIV or children), consisting of a combination of one or two screening tests and a diagnostic evaluation (Annex 1). Algorithms for screening people living with HIV are discussed in Chapter 5 and algorithms for screening children in Chapter 6. The algorithms differ in sensitivity and specificity and, therefore, have different yields of detection of prevalent TB, predictive values and associated costs. The performance of the algorithms also depends on the prevalence of TB in the population being screened. T ables A2.1-A2.3 in Annex 2 contain modelled estimates of the performance of the algorithms described below, including the results of true- and false-positive diagnoses for the entire algorithm, consisting of the screening test(s) followed by diagnostic evaluation with an mWRD. For all algorithms, the risk of a false-positive diagnosis increases as the prevalence declines; therefore, special attention must be paid to diagnostic accuracy of the screening algorithm, particularly when the prevalence of TB in the screened", "population is < 1%. At a TB prevalence of 0.5% in the screened population, all the algorithms have a positive predictive value of < 75% (i.e. 25% give a false-positive diagnosis). Efforts must therefore be made to ensure high-quality diagnostic procedures and clinical assessment, especially when the TB prevalence in the screened population is moderate to low. In each given screening situation, it is critical to consider the proportions of false-positive and false- negative results that are unacceptable. Ethical considerations such as unnecessary anxiety and inappropriate TB treatment due to a false-positive diagnosis and the adverse consequences of missing or delaying a TB diagnosis should guide the acceptable sensitivity and specificity of the algorithm. Considerations will depend on risk groups. For groups of individuals who are at high risk of dying or of other severe negative effects of a missed or delayed diagnosis and treatment, however, the algorithm used should have very high sensitivity, even at the expense of lower specificity. The algorithms have different costs and requirements in terms of human resources and health systems. The choice of algorithm depends on the risk group, the prevalence of TB, the availability of resources and the feasibility of implementation. Algorithms that begin with screening for cough Fig. A.1.1 \u2013 Screening with cough (page 60) Fig. A.1.2 \u2013 Parallel screening with cough and CXR (page 61) Fig. A.1.3 \u2013 Sequential positive serial screening with cough and CXR (page 62) Fig. A.1.4 \u2013 Sequential negative serial screening with cough and CXR (page 63)", "Chapter 3. Screening tools and algorithms 37 Algorithms that begin with screening for any symptom compatible with TB Fig. A.1.5 \u2013 Screening with any TB symptom (page 64) Fig. A.1.6 \u2013 Parallel screening with any TB symptom and CXR (page 65) Fig. A.1.7 \u2013 Sequential positive serial screening with any TB symptom and CXR (page 66) Fig. A.1.8 \u2013 Sequential negative serial screening with any TB symptom and CXR (page 67) Algorithm that begins with screening with CXR (page 68) In addition to the parallel and sequential algorithms that include CXR above, the algorithm in Fig A.1.9 presents an option to screen only with CXR, followed by referral for diagnostic evaluation for people with an abnormal CXR. Algorithm that begins with screening with mWRD (page 69) The algorithm in Fig A.1.10 presents a screening approach that begins with an mWRD, followed by a thorough clinical evaluation (including physician assessment and further tests such as CXR or repeat mWRDs on additional sputum samples) for those with a positive test result. 3.2.3 Choosing an algorithm for a screening programme The choice of screening and diagnostic algorithms should be based on: \u2022 the specific objectives of screening; \u2022 the accuracy and yield of the screening and diagnostic tests (see table of modelled performance in Annex 2); \u2022 the profile of the prioritized risk groups; \u2022 the TB prevalence in the risk groups; \u2022 the costs, availability and feasibility of different tests; and \u2022 the ability to engage the population to be screened. The specific objectives of screening partly determine the relative importance of the sensitivity of the algorithm as compared with its specificity, as well as the trade-off between cost and yield or potential epidemiological impact. For example, if one objective is to determine eligibility for TPT (for example, as part of an investigation of contacts, people living with HIV or other populations or individuals who may benefit from TPT), it is critical to have very high sensitivity (and thus very high negative predictive value of a test result), even if the specificity is suboptimal (which in this case might lead to referral of additional people for diagnostic evaluation and possibly unnecessary treatment for TB disease). In other situations, it may be critical to avoid false-positive diagnoses and maximize efficient use of limited resources for diagnostic evaluation, and a less sensitive but highly specific algorithm might be preferable, such as a clinic-based screening", "programme in a densely populated urban area, in which laboratory capacity and the supply of cartridges for diagnostic testing would be rapidly depleted if a screening and diagnostic algorithm with low specificity was used. The profile of the risk group can influence the choice of algorithm because the accuracy of certain tools is affected by underlying biological factors associated with certain risk factors (for example, CXR screening is less sensitive in people living with HIV). Certain considerations for the best algorithms for specific risk groups are based on their risk for TB and for unfavourable outcomes if TB is not detected early and logistical considerations in screening specific to the risk group and the location in which screening is conducted (see further discussion below). The prevalence of TB in a risk group directly affects the predictive values of all tests and therefore the occurrence of true or false results. The lower the prevalence, the more important it is that the algorithm has very high specificity, in order to avoid a high proportion of false-positive diagnoses. The total cost of an algorithm depends on the unit cost of each test (including start-up and running costs), the total number of tests required and the overhead costs for delivering the services.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 38 Different algorithms require different numbers of tests for any given population with any given TB prevalence. The tables in Annex 2 provide the estimated numbers of tests required for different algorithms in relation to case-detection yield. The tool described in 3.3 can be used to generate cost estimates for each algorithm and risk group according to local cost assumptions. This information can be used to conduct a simple cost\u2013effectiveness analysis of the cost per true case detected. The availability, cost and feasibility of tests may, however, differ considerably in different parts of the health-care system. Outreach screening requires consideration of mobility and field conditions. For example, digital CXR technology offers lower running costs and greater mobility than conventional CXR but requires a high initial investment. Symptom screening may be relatively low cost, especially in integrated services, but it is also relatively insensitive. Diagnostic evaluation may become more feasible under outreach conditions if proper sputum collection and transport can be organized. The additional resources required to implement TB screening should not discourage managers from investing in this intervention but should stimulate mobilization of the necessary funds. Consideration must be given to the ability to engage with the population to be screened. Although the algorithm used will have significant implications for the budget and logistics, so too will the approach used to conduct screening. Contact investigation might require home visits, or individuals with TB can be requested to bring their contacts to a health facility to be tested. Although the latter option may be far cheaper, far fewer people may actually be screened. Similarly, community outreach may involve setting up mobile treatment teams and laboratories, home visits or simply using loudspeakers to announce the availability of testing services. Different approaches work differently in different settings, and their impact will depend on the number of people reached and tested and on the yield. The acceptability of a given test and the beliefs of people who are screened and health- care workers may have to be considered. Out-of-pocket expenditure required to complete screening should also be considered. Considerations for algorithms for risk groups The prevalence of TB and risks of poor health outcomes or mortality, logistical factors associated with the likely location of screening and considerations for initiating TPT for certain risk groups all influence the choice of screening algorithm. Certain algorithms inevitably", "require more resources, and therefore resource availability will likely determine which algorithm is feasible. Contacts As close contacts of individuals with TB have a high prevalence of TB, their high risk of TB and their eligibility for TPT indicate urgent screening of this risk group. As the goal of screening in this group is to identify TB disease early and to rule out TB accurately, a highly sensitive algorithm is preferred \u2013 if possible one that begins with CXR because of its high sensitivity and specificity. Screening of contacts should ideally begin in the patient\u2019s household to ensure high coverage of this risk group. Thus, either transport of the patient to a nearby health facility or mobile CXR will be required to implement CXR- based algorithms in this risk group. The cost of such screening will be substantial, but this risk group is smaller than other groups. Although a CXR-based algorithm is preferred for this group, a more feasible algorithm must be selected when CXR services are not yet available for the screening programme. Miners A CXR-based screening approach, together with screening for symptoms of TB and lung disease, is also preferred for miners exposed to silica, given their high risk of lung disease (including TB) and lung damage from silicosis. Large mines often have facilities on site to conduct CXR screening for employees; smaller, informal mines may have limited capacity and may have to use other providers while increasing capacity.", "Chapter 3. Screening tools and algorithms 39 Prisoners Given the high risk of transmission in this group, a highly sensitive algorithm beginning with CXR is preferred. Larger prisons and penitentiary institutions may have radiography capacity on site or can bring mobile vans for screening campaigns. In smaller institutions or locations where CXR capacity is not available, screening algorithms based on symptoms or mWRD may be acceptable until CXR services are available. People with clinical risk factors In settings where the general TB prevalence is > 100/100 000, TB screening may be conducted among people with TB risk factors who are seeking health care for any medical reason or among those who are in health care. Access to radiography is more likely in a health facility. This can maximize screening sensitivity. Symptom screening is also valuable for immediate decisions on triage and infection control. General population and communities with structural risk factors For screening in the community, in populations with structural risk factors for TB and/or in the general population when the TB prevalence is \u2265 0.5%, a highly sensitive screening algorithm will provide the highest yield in terms of maximizing case detection, as substantial work is usually required to take intervention activities into the field. Such an algorithm, however, requires substantial resources for implementation. Screening for symptoms is much easier but is less sensitive and specific, depending on the symptom approach, and has a smaller potential impact on population prevalence or transmission. Screening with mWRDs is highly accurate (particularly specific) but has substantial resource implications. 3.3 ScreenTB tool The most desirable screening strategy is one with high total yield of true-positive TB cases, few false-positives, low NNS, low cost, a rapid and simple algorithm and high client acceptability. In practice, many of these factors can run in opposite directions, and multifactorial analysis is required. The ScreenTB online tool has been developed to assist in prioritizing risk groups for screening and choosing appropriate screening and diagnostic algorithms. The tool allows users to select one or several risk groups and to estimate the yield and costs of screening for each with different screening algorithms. The tool must not be used as the only source for prioritization, planning and budgeting but rather as a starting point. The tool can be found at https://www.who.int/activities/screening-for-tb.", "Chapter 4. Implementation of CAD technologies in a new setting 41 Chapter 4. Implementation of CAD technologies in a new setting 4.1 Considerations in selecting and using CAD for screening in TB programmes CAD technologies for automated reading of digital CXR for TB detection offer a promising solution for high-TB burden countries; however, selecting the appropriate CAD product for a particular setting can be complex. When selecting a CAD product, TB programmes and implementers should consider multiple aspects of the technology and its interface with existing infrastructure, including: \u2022 national and international regulatory approval of the products; \u2022 the accuracy of the product for detecting abnormalities consistent with TB; \u2022 the requirements for running the CAD programme, including: \u2013 the requisite software and hardware. Most CAD products can be run on any digital radiography platform, but not all. This consideration should include options for integration with existing and legacy systems. \u2013 the Internet connectivity required to run the programme. Although online deployment is the most common method of implementation, access to a stable Internet connection may be difficult. \u201cCloud-based\u201d CAD programmes require stable Internet to function, and most CAD developers offer offline solutions that can be operated independently of Internet connection, although the cost may vary. \u2022 the cost of running CAD. Pricing schemes for CAD programmes vary widely according to factors such as: bundled costs (whether hardware will be purchased with software), the costs of installation and set-up and the costs of reading. Each automated reading may be priced per CXR (usually volume) or structured as a set price for unlimited use for a certain time. Maintenance costs should also be considered. \u2022 data security and privacy. Commercial cloud servers are used for online deployment by default. Countries are, however, increasingly concerned about privacy and request that servers be set up within their borders. Local or in-country servers could be set up, although at additional cost. When CXRs are analysed via commercial cloud servers, images will have to be anonymized before uploading. Most CAD solutions include an anonymization tool. The market of CAD products for TB detection is constantly changing and expanding, with new versions of products and new companies coming online almost every day. FIND and the Stop TB Partnership have jointly created an online data repository of the CAD products currently available on the market and their key characteristics as described above, based on results of surveys", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 42 Effective integration of CAD products into routine TB screening or triage requires determination of an appropriate CAD threshold that will be used to signal a positive screen and trigger further TB diagnostic evaluation. As threshold values for CAD products are not static or consistent across software or even versions of the same software, the user must determine the most appropriate abnormality or threshold score for their setting and use case, above which a confirmatory diagnostic test would be conducted. Identifying the ideal threshold for each use of CAD requires decisions on the goals and acceptable costs of screening. As with other screening tools, there is an inherent trade-off in the selection of the threshold score; lower scores will maximize the sensitivity of the tool to detect true TB patients in the population being screened but will incur additional costs for diagnostic testing because of reduced specificity. Higher scores will reduce the volume, and thus costs, of diagnostic testing and will probably focus case detection on more severe cases, but the reduced sensitivity will result in missed cases (Fig. 4.1). Fig. 4.1 Sensitivity vs specificity over the CAD threshold spectrum Diagnostic evaluation cost CAD threshold score 0 maximum score Specificity Sensitivity Proportion of prevalent TB detected CAD can be integrated into TB screening or triage when human interpretation is not available, or it can be used with trained readers to reduce the workload. \u2022 CAD can be used for initial screening, with any abnormal result referred to a human reader for final reading. \u2022 CAD can be used for initial screening, with a portion of all results verified by a human reader (e.g. all abnormal and 10% of normal CAD results). \u2022 CAD can entirely replace a human reader, with all abnormal results referred for diagnostic evaluation. \u2022 CAD and human reading can be done in parallel, with an abnormal reading from either reading referred for diagnostic evaluation. The performance of CAD in terms of the sensitivity and specificity of a particular threshold score are likely to depend on TB epidemiology and subgroups, such as people living with HIV and older people. Threshold scores also differ substantially by CAD product and even among versions of the same software. Determination of appropriate threshold scores based on local realities is therefore an integral part of the set-up and use of CAD and", "Chapter 4. Implementation of CAD technologies in a new setting 43 4.2 Toolkit for CAD calibration to enable implementation A toolkit has been developed jointly by the WHO Global T uberculosis Programme and the Special Programme for Research and T raining in T ropical Diseases for conducting a CAD calibration study in a new setting. The toolkit consists of three parts. \u2022 Part A introduces CAD calibration studies, including their designs, outcomes of interest and guidance for interpreting study findings and their application in a TB programme. \u2022 Part B is a generic study protocol, with the proposed research method, data collection and analysis. The protocol can be adapted by users to seek ethics approval. Detailed information assists users in conducting operational research, including study procedures and sample size estimates for various study designs and sampling options, a generic study protocol, data collection tools and an online tool for data analysis. \u2022 Part C is a guide to use of an online tool, \u201cCAD for TB detection\u201d, to support data analysis, to determine appropriate thresholds by demonstrating the practical implications of various CAD thresholds, including for true- and false-positive CAD readings and the costs incurred for follow up confirmatory testing. Part C also includes case studies and guidance to help users interpret the results generated by the online tool and their practical application to local contexts. The full toolkit can be found online at https://tdr.who.int/activities/calibrating-computer-aided- detection-for-tb. In general, a CAD calibration study requires identification of the population in which CAD is to be used, sampling of the population to obtain CAD scores and the TB status of a subset of the population, and use of that data to calculate the sensitivity and specificity of CAD at different potential thresholds. The implications of the thresholds in terms of yield of true- and false-positive cases detected and the cost of diagnostic evaluation can then be used to guide the choice of a CAD threshold for a given implementation according to the goals of the screening or triage programme. 4.3 Online tool for calibration of CAD in a new setting The CAD for TB detection calibration tool has been developed for analysis of the data collected in the CAD calibration protocol described above. The tool estimates the primary outcomes of yield and cost at every possible CAD threshold, including yields of true-positive, true-negative, false-positive and false-negative results; sensitivity and specificity; negative and positive", "predictive values; proportions of prevalent TB cases diagnosed and missed; and cost implications, including total costs for diagnostic evaluation and cost per true case detected. These values are then used to construct a ROC curve to illustrate the sensitivity and specificity of CAD at a range of possible thresholds. These outputs allow users to visualize potential scenarios and to select a threshold score for a given CAD implementation according to the objectives of the screening programme, the desired accuracy and yield, and the cost implications. The tool also allows users to conduct sub-population analyses for specific patient characteristics, such as separate ROC curves and threshold calculations for individuals who are HIV- positive or who are over 55 years of age. The tool can be found online at https://tdr.who.int/activities/ calibrating-computer-aided-detection-for-tb.", "Chapter 5. Screening for tuberculosis disease among adults and adolescents living with HIV 45 Chapter 5. Screening for tuberculosis disease among adults and adolescents living with HIV The algorithms for screening adults and adolescents \u2265 10 years of age living with HIV are presented in Fig. A.3.1-A.3.11 in Annex 3 . 5.1 Introduction Since 2011, WHO has recommended that people living with HIV be systematically screened for TB disease at each visit to a health facility. The recommendation is based on the high risk of this group for TB and mortality and a lingering gap in case detection in this population. In 2019, people with HIV were at 18 times greater risk for incident TB than people without HIV and close to one third of deaths from AIDS were due to TB (2). Only 56% of the total estimated number of HIV-positive incident TB cases were detected in 2019 (2). Early detection and timely treatment of TB among people living with HIV is critical for reducing mortality. T o date, the recommendation has been to screen for four primary symptoms of TB among people living with HIV: cough, fever, weight loss or night sweats. Screening with the WHO four-symptom screen (W4SS) is recommended for all people living with HIV at every encounter with a health-care worker, both to detect prevalent TB disease and to rule it out before initiation of TPT . Recent evidence indicates, however, that the accuracy of W4SS may be suboptimal for certain subpopulations living with HIV (35). Therefore, for the 2021 update to the TB screening guidelines, a systematic review and a meta-analysis of individual patient data were commissioned to evaluate the performance of W4SS and alternative screening tools among subpopulations of people living with HIV , each with distinct clinical characteristics and implications for implementation: \u2022 Outpatient people living with HIV not receiving ART: This population may include people with newly diagnosed HIV , those who discontinued ART and are re-engaging in care and those who experience ART failure. This subpopulation is at a high risk of TB disease or reactivation because of their probably weakened immune system. They are also at greater risk of death, and therefore a highly sensitive and specific screening strategy is required to ensure rapid initiation of treatment for TB disease or infection, as appropriate. Ideally, TB screening in this population will be accompanied by prompt enrolment in HIV/AIDS care", "and initiation of ART . Staging of HIV disease and testing to exclude TB with LF-LAM and mWRD is recommended in people with advanced HIV disease (12). \u2022 Outpatient people living with HIV on regular ART: Once in regular ART care, this population is likely to have suppressed viral replication of HIV and therefore a reduced viral load and significant immune recovery. This decreases the chances of TB reactivation and incident disease. Thus, this population is at lower risk of TB and has a physiological presentation similar to that of", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 46 non-HIV-infected screening participants. People living with HIV who are currently in care should be screened for TB at every regular contact with the health services as part of integrated HIV care. \u2022 Medical inpatients living with HIV: This population is usually at an acute state of illness and requires immediate care, including screening, diagnostic evaluation and treatment, to decrease the risk of death. Regardless of their ART status, people living with HIV should be screened for TB at any episode of hospitalization. \u2022 Pregnant women living with HIV: This is a key population, given the suppressed immune status of the mother and the importance of protecting the health of the fetus. TB screening for this population should be integrated with prevention of mother-to-child transmission and antenatal care. \u2022 Children < 10 years living with HIV: This subpopulation is addressed in 6.3. Health-care workers should suspect TB in any person living with HIV . People with HIV who screen negative for TB and show no evidence of TB disease should be offered TPT if they are eligible. 5.2 Screening tools 5.2.1 WHO-recommended four-symptom screen W4SS was first recommended in 2011, with an initial recommendation for systematic screening of all people living with HIV at every visit to a health-care facility. W4SS is a simple screening approach that is non- invasive, does not require infrastructure (technology, electricity, Internet) and is feasible to implement in any setting. The results of a symptom screen are, however, subjective and depend on the patient\u2019s level of understanding and their willingness to share their physical experience of symptoms and on the provider\u2019s interpretation of the patient\u2019s self-reported symptoms. Thus, the quality and consistency of the W4SS is likely to vary among clinical settings. T able 5.1 shows the accuracy of W4SS in different sub-populations of adults and adolescents living with HIV . The latest evidence review for the 2021 guidelines showed that W4SS has relatively high sensitivity in adults and adolescents living with HIV , 83%, but low specificity, 38%. The sensitivity of W4SS among outpatients on ART is relatively low, 53%, indicating that W4SS alone would not be sufficient to detect TB among people in regular ART care. W4SS also has low sensitivity in pregnant women living with HIV . It is relatively sensitive in outpatients not on ART (84%), indicating that W4SS is useful", "Chapter 5. Screening for tuberculosis disease among adults and adolescents living with HIV 47 Table 5.1 Diagnostic accuracy of W4SS in different subpopulations of adults and adolescents with HIV Population Sensitivity (%) Specificity (%) All people living with HIV 83 38 Inpatients 96 11 Outpatients on ART 53 70 Outpatients not on ART 84 37 \u2264 200 CD4 cells/\u00b5L a 86 30 Pregnant women living with HIV 61 58 For more detail, see Web Annex B of the screening guidelines. a Indicator of advanced HIV disease In view of its exceptionally low specificity among medical inpatients, W4SS is not a suitable tool for screening in this population, as the resulting high positivity rate renders it clinically useless for indicating further care. Given the severity of the disease and the need for rapid action in this acutely ill population, other tools may be necessary. Nonetheless, W4SS is an essential part of the clinical examination of most subpopulations and is the most accessible screening tool at all levels of the health system. It can be repeated as often as necessary, while more intense screening strategies might be used less frequently, such as at annual check-ups. Familiarity with W4SS is already widespread in many HIV services as a result of capacity- building and supervision. It also has an important role in ruling out TB disease due to its high negative predictive value in most settings. This is important in the preventive TB care pathway of people with HIV who would benefit from TPT in the absence of TB disease. 5.2.2 C-reactive protein (CRP) C-reactive protein (CRP) is an indicator of systemic inflammation that can be measured with a blood test. A point-of-care test is available that is performed on capillary blood collected from a finger-prick, making it simple, affordable and feasible in primary care. The turnaround time from testing to result with many CRP test kits is 3\u20135 min, allowing a quick clinical decision to refer a patient for diagnostic evaluation for TB disease or initiation of TPT . An additional potential benefit of CRP is that it can alert clinicians to the presence of other diseases, such as bacterial pneumonia, bronchitis or other infectious or non-infectious conditions (e.g. lymphoma). Health staff and patients may be more confident in the results of a biochemical test than of a more subjective symptom screen. The threshold for considering a result as abnormal may differ by", "setting. Evidence for the use of a cut-off value of > 5 mg/L or > 10 mg/L was reviewed for the screening guideline; both were found to have the necessary accuracy for detecting TB disease. Currently, the cut-off value of > 5 mg/L is recommended, as it is the lowest threshold indicating abnormality in many clinical settings and because it is the most sensitive. At this cut-off, CRP has a similar sensitivity and higher or similar specificity to symptom screening in all subpopulations of adults and adolescents living with HIV tested (T able 5.2, and see Web Annex B of the screening guidelines). CRP shows clinically significantly greater sensitivity and specificity than W4SS among outpatients living with HIV who are not on ART (CRP , sensitivity 89% and specificity 54%; W4SS, sensitivity 84% and specificity 37%). CRP can also be used in combination with W4SS. While a parallel approach will have resource implications because CRP ? FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms #35", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 48 of the higher sensitivity and lower specificity, data reviewed for the 2021 guideline revision support sequential combination of a positive W4SS followed by CRP with a cut-off of > 5 mg/L, particularly for people not on ART (see 5.4, and Web Annex B of the screening guidelines). CRP can play an important role in ruling out TB disease before initiation of TPT, which is essential in this population, and requires a test with the highest possible negative predictive value. CRP with a cut-off of > 5 mg/L had a negative predictive value of 99.8% among outpatients not on ART in a setting with a 1% prevalence of TB. Table 5.2 Accuracy of CRP with cut-off values of > 5 mg/L and > 10 mg/L compared with a culture reference standard Population Cut-off > 5 mg/L Cut-off > 10 mg/L Sensitivity (%) Specificity (%) Sensitivity (%) Specificity (%) All people living with HIV 90 50 83 65 Inpatients 98 12 97 21 Outpatients on ART 40 80 20 90 Outpatients not on ART 89 54 82 67 \u2264 200 CD4 cells/\u00b5L a 93 40 90 54 Pregnant women living with HIV 70 41 70 54 For more detail, see Web Annex B of the screening guidelines. a Indicator of advanced HIV disease 5.2.3 Chest X-ray CXR is useful for screening people living with HIV for TB. It is currently recommended by WHO for use in parallel with W4SS for ruling out TB disease before initiating TPT . Similarly, CXR can be used in parallel with W4SS to screen for TB disease, a positive or abnormal result on either screen indicating referral for diagnostic evaluation. CXR can be used to either add to the sensitivity of W4SS (in a sequential negative algorithm) or to improve the pre-test probability of TB among those who screen positive for symptoms (in a sequential positive algorithm) (see 3.2). Reading modalities of \u201cany abnormality\u201d or \u201cabnormality suggestive of TB\u201d can be used, depending on the context, the availability of radiological expertise, resources and a preference for higher sensitivity or higher specificity. T able 5.3 shows the diagnostic accuracy of CXR combined with W4SS in different sub-populations of people living with HIV . A combined screening strategy of W4SS and CXR offers a significant improvement in sensitivity, particularly for screening outpatients enrolled in ART care, over W4SS", "Chapter 5. Screening for tuberculosis disease among adults and adolescents living with HIV 49 Table 5.3 Diagnostic accuracy of W4SS combined with CXR (any abnormality) in different subpopulations of people living with HIV as compared with a culture reference standard, with a positive or abnormal result on either or both screens Population Sensitivity (%) Specificity (%) All people living with HIV 93 20 Inpatients 90 7 Outpatients on ART 85 33 Outpatients not on ART 94 19 \u2264 200 CD4 cells/\u00b5L a 94 14 Pregnant women living with HIV 75 56 For more detail, see Web Annex B of the screening guidelines. a Indicator of advanced HIV disease 5.2.4 WHO-recommended rapid molecular diagnostic tests mWRDs are now also recommended for screening people living with HIV . (See 3.1.4 for a full description of their use in screening). A positive mWRD screen result in a person with HIV must be followed by further diagnostic evaluation to confirm or rule out TB. Among medical inpatients in settings where the prevalence of TB is \u2265 10%, mWRDs are strongly recommended for screening for TB disease because of the severity of illness in this population. As rapid diagnosis and care are required, a positive mWRD result in this population can be considered an indication for treatment and need not be followed by a separate diagnostic evaluation, while ensuring proper monitoring of treatment response and evaluation for alternative diagnoses, particularly if the patient had TB in the previous 5 years. T able 5.4 shows the accuracy of mWRD screening in different sub-populations of adults and adolescents living with HIV . The overall sensitivity of mWRD in all people living with HIV is estimated to be 69% and the specificity 98%, while W4SS followed by a mWRD is estimated to have a sensitivity of 62% and a specificity of 99% (see Web Annex B of the guidelines). The accuracy of mWRD in most sub- populations is not significantly different from that of W4SS followed by mWRD. Table 5.4 Diagnostic accuracy of mWRD for screening for TB in different subpopulations of people living with HIV as compared with a culture reference standard Population Sensitivity (%) Specificity (%) All people living with HIV 69 98 Inpatients 77 93 Outpatients on ART 54 99 Outpatients not on ART 72 98 \u2264 200 CD4 cells/\u00b5L a 76 97 Pregnant women living with HIV 55 99 For more detail, see Web", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 50 5.3 Considerations for use of all screening tools All the screening tests described above, when positive or abnormal, identify adults and adolescents living with HIV who have a higher probability of TB disease and who are to be referred for diagnostic evaluation. TB diagnosis among people living with HIV should include use of an mWRD as a diagnostic test (12), LF-LAM where indicated (12), and other clinical, radiological or laboratory procedures for detecting pulmonary and extrapulmonary TB as necessary. When a screening test or algorithm is used and the results are normal or negative, if the algorithm has sufficient negative predictive value in the setting, patients should be referred for evaluation for TPT . TPT is strongly recommended for people living with HIV in whom TB disease has been ruled out (4). As part of scale-up, tools should first be included in the guidelines of national TB and HIV programmes and in national algorithms for screening and diagnostic care for people living with HIV (see 5.4 and Annex 3 for further discussion of screening algorithms for people living with HIV). Health staff will require adequate training in use of each tool, and the results of each screening test conducted should be recorded in patient clinical records. New screening tools should not replace W4SS, which should continue to be conducted at every encounter with a health-care worker or peer supporter, regardless of the inclusion of new screening tools in the algorithm. The W4SS strengthens interpretation of the results obtained with other screening tests and is also valuable for immediate infection control measures. W4SS is also critical for indicating eligibility for an LF-LAM test if a CD4 cell count is not available (12). Countries should include new tools for screening people living with HIV in national TB screening algorithms according to feasibility, level of health facility and available resources. Lack of access to any of the tools described in this section should not be a barrier to TB screening or ruling out TB in order to allow initiation of TPT . Implementation considerations for CXR Interpretation of CXR images for people living with HIV CXR requires interpretation by a radiologist, other trained health personnel or CAD software. CXR findings may differ widely in people with HIV-associated TB, from a completely normal picture to multiple radiological abnormalities typically associated with advanced TB", "disease (36). Periodicity of CXR screening Although no data are available on the optimal periodicity of CXR screening, a pragmatic approach would be to perform CXR annually among outpatients living with HIV at the time of viral load testing or other investigations, in addition to W4SS at every encounter with a health worker between annual screens. The frequency might be determined according to the regularity of ART, use of TPT and TB transmission setting. A baseline CXR and access to imaging taken previously are useful for comparing subsequent radiological changes. (See 3.1.2 for further considerations for screening with CXR). Service delivery HIV services should be integrated with TB and radiography services to maintain a \u201cone-stop shop\u201d. It is essential to engage with local civil society organizations, given that this screening approach is most relevant for people living with HIV who are stable, in care, immunocompetent and likely to be supported in the community. The risks of exposure to ionizing radiation might be a greater concern for this group, who undergo CXR regularly and may also receive radiography to evaluate health problems between screenings.", "Chapter 5. Screening for tuberculosis disease among adults and adolescents living with HIV 51 Implementation considerations for CRP Choice of cut-off value CRP at cut-off values of either > 5 mg/L or > 10 mg/L is similar to or more accurate than W4SS. The cut-off of > 5 mg/L is recommended because it is the lowest threshold that indicates abnormality in many clinical settings and is more sensitive. The choice of cut-off value will, however, depend on the availability of CRP technology, the prevalence of other conditions that may increase CRP values and a preference for increased sensitivity or increased specificity. Requirements and service delivery Currently, many analysers are available for measuring CRP at points of care, with different levels of detection, although all can be used for TB screening with a CRP cut-off between 5 and 10 mg/L. The results obtained with most quantitative point-of-care analysers are strongly correlated with those of laboratory analysers. Like finger-stick measurement of glucose with a glucometer, point-of-care CRP tests provide rapid (\u2264 5 min) quantitative results from capillary blood (obviating the need for phlebotomy) and are simple enough to be performed by front-line health-care workers after minimal training. Containers for safe disposal of needles and other sharp tools for pricking the finger must be available, and other infection control measures in the collection of blood must be followed. The overall laboratory requirements are minimal; however, most analysers require a continuous electricity source, and most CRP assays require cold storage and refrigeration (+2 to +8 \u00b0C). Some semi-quantitative test strips are available with operational characteristics ideal for use in remote settings (inexpensive, no analyser required); however, the agreement of results with those of laboratory analysers is moderate and may decrease further if time-to-test strip interpretation exceeds 5 min. If point-of-care testing for CRP is not available, blood samples will have to be sent to the nearest laboratory, which will significantly undermine the utility of the test for on-the-spot decision-making and render it less useful for screening in outpatient settings. Implementation considerations for mWRD Resource requirements Use of mWRDs for screening in addition to diagnostic testing represents a significant shift and requires significant resources. (See Annex 3 on modelled algorithms.) Providers and health staff require training in the proper use and interpretation of mWRDs when used for screening. Service delivery Depending on feasibility and available resources, countries may choose to prioritize TB screening with mWRDs", "in certain subpopulations other than those for whom it is generally recommended, such as all medical inpatients or pregnant women living with HIV . Use of mWRDs for screening among outpatients with HIV in regular ART care should be aligned with regular HIV services (e.g. viral load monitoring). Similarly, for pregnant women with HIV , it should be aligned with antenatal services. T o use mWRDs to screen medical inpatients with HIV , the TB prevalence in medical wards may be calculated as the percentage of admissions that are diagnosed with TB among hospital inpatients living with HIV , during a recent 6\u201312-month period. See 3.1.4 for further considerations on screening with mWRDs.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 52 5.4 Algorithms for screening Eleven algorithm options are proposed for screening of people living with HIV for TB that include the new and existing screening tools presented in this section (see Annex 3 ). (See 3.2 for an introduction and discussion of screening algorithms in general, including the definitions and implications of single, parallel, sequential positive and sequential negative screening algorithms.) The algorithms focus on screening and referral to a diagnostic evaluation, including an mWRD test, although LF-LAM should be used where indicated to enhance early detection of TB (12). Each algorithm has a different sensitivity and specificity and therefore different potential for true-positive, true-negative, false-positive and false-negative results. The yields of TB and predictive values also depend on the prevalence of TB in the population being screened. For all algorithms, the risk of a false-positive diagnosis increases as the prevalence decreases; therefore, attention must be paid to diagnostic accuracy, particularly when the prevalence of TB in the screened population is low. The algorithms, when combined with mWRD for diagnosis, have different costs and requirements in terms of human resources and health systems. Which algorithm is chosen for screening and diagnosis depends on the risk group, the prevalence of TB, the availability of resources and the feasibility of implementing the algorithm. The tables in Annex 4 show modelled estimates of the performance and outcomes of the screening algorithms described below, including the results of true- and false- positive diagnosis for the entire algorithm, consisting of the screening test(s), followed by diagnostic evaluation with an mWRD. Algorithm options Fig. A.3.1 W4SS single screening algorithm (page 76) Fig. A.3.2 CRP single screening algorithm (page 77) Fig. A.3.3 CXR single screening algorithm (page 78) Fig. A.3.4 Parallel screening algorithm with W4SS and CRP (page 79) Fig. A.3.5 Sequential positive screening algorithm with W4SS and CRP (page 80) Fig. A.3.6 Sequential negative screening algorithm with W4SS and CRP (page 81) Fig. A.3.7 Parallel screening algorithm with W4SS and CXR (page 82) Fig. A.3.8 Sequential positive screening algorithm with W4SS and CXR (page 83) Fig. A.3.9 Sequential negative screening algorithm with W4SS and CXR (page 84) Fig. A.3.10 mWRD single screening algorithm for medical inpatients in settings with TB prevalence > 10% (page 85) Fig. A.3.11 mWRD single screening algorithm for people living with HIV (page 86)", "Chapter 6. Screening for tuberculosis disease in children 53 Chapter 6. Screening for tuberculosis disease in children The algorithms for screening children are listed in Fig. A.5.1-A.5.6 in Annex 5 . 6.1 Introduction It is estimated that, in 2019, approximately 1.2 million children under 15 years of age fell ill with TB, and 230 000 died of TB (2). In about 56% of the 1.2 million patients, TB was not diagnosed or reported, the proportion being highest in children < 5 years of age (65%). The symptoms of TB are under- recognized in children because they are less specific and overlap with those of common childhood diseases, often leading to delayed diagnosis. Children are more prone to extrapulmonary forms of TB, which may challenge timely detection. Certain forms, especially TB of the central nervous system, carry a high risk of death or permanent disability when detected late, even if treated. Screening children for TB disease is imperative to detect TB earlier, start treatment earlier and increase the likelihood of better treatment outcomes. As children frequently have extrapulmonary TB disease with or without pulmonary involvement, health-care workers must be aware of symptoms that indicate TB at other sites (such as lymphatic, abdominal, meningeal and osteoarticular TB). TB meningitis, disseminated TB and spinal TB are medical emergencies that must be recognized quickly and immediately referred to the appropriate level of care. The risks of severe disease and death from TB can be reduced by BCG vaccination (37, 38); however, the considerations for screening discussed in this section apply regardless of immunization status. The children who should be targeted for screening are those who are at particularly high risk of TB disease, especially those in close contact with someone with TB and children aged 0\u201310 years who are living with HIV . Screening of adolescents (10\u201319 years) living with HIV is discussed in Chapter 5 of this handbook. Countries are encouraged to monitor and evaluate the yield of TB screening approaches among children to be screened, including child close contacts and children living with HIV , disaggregated by screening tool and algorithm, to broaden the evidence base of the yield, costs, safety and clinical outcomes of different strategies. 6.2 Screening child contacts of patients with TB Child contacts are at high risk of TB disease, and the risk varies substantially by age. Newborn infants are at particularly high risk of infection with TB", "if the mother had untreated TB disease when they were born. Apart from the risk of exposure because of close proximity to adults in a household with TB, children < 5 years who are infected with TB have a 19% chance of progression to TB disease within 2 years (39). Most paediatric mortality occurs in this age group, with 80% of paediatric deaths from TB occurring in children < 5 years (40). An infant infected with TB has a very high risk of rapidly developing TB disease and dying. Among infants (< 1 year) infected with M. tuberculosis, 20\u201350% will develop TB disease, almost all of them within 1 year of infection (39-41). The risk of progression to TB disease among older children and adolescents (5\u201314 years) in the 2 years after TB infection is", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 54 somewhat lower but still consequential, at 9% (39). The high risk of progression to TB disease and the associated high mortality rates underline the importance of screening children exposed to close contacts with TB. 6.2.1 Symptom screening Any child < 15 years who has had close contact with someone with TB disease should be screened for TB with a symptom screen and/or CXR as part of active contact-tracing (see Algorithm A.5.1 in Annex 5). Symptoms that should be used to screen for TB are cough, fever and poor weight gain (or weight loss). In young children, reduced playfulness or lethargy should also be included in symptom screening; cough may be absent. It is useful to examine growth charts regularly to determine whether a child has been losing weight or their weight has plateaued. A plateau in weight gain should be a warning sign for possible TB. In the latest review, a symptom screen in which a child has any of the symptoms of cough, fever or poor weight gain has a sensitivity of 89% and a specificity of 69% for TB disease (against a composite reference standard) (see Web Annex B of the screening guidelines). The low specificity of a symptom screen alone means that about 30% of children may undergo unnecessary diagnostic tests or even treatment for TB. The risk of a false-positive diagnosis of TB after a false-positive symptom screen among children may be higher than for adults because such a diagnosis is frequently made solely on clinical grounds. Because of the high rates of mortality and morbidity among children with TB, however, the risk of a missed diagnosis is generally judged to outweigh the risk of a false diagnosis and unnecessary TB treatment, especially because children generally tolerate TB treatment and TB preventive treatment well. Health-care workers should nonetheless remain vigilant to possible false-positive TB diagnoses among children, monitor their response to treatment carefully and consider alternative causes, especially if a child is not improving on treatment. If a plausible alternative diagnosis is confirmed, providers may consider stopping TB treatment while remaining mindful that TB may co-exist with other diseases. 6.2.2 CXR The sensitivity for TB of \u201cany abnormality\u201d as reported on CXR in children is 84%, and the specificity is 91%. It is thus more specific than symptom screening alone. The estimates of the accuracy", "of CXR are not, however, disaggregated by age group, and significant differences in CXR findings between younger and older children may lead to important differences in sensitivity and specificity by age group. Abnormalities caused by TB seen on CXR in children may differ widely from those in adults. While older children may have \u201cadult type\u201d disease presentation, such as cavitary disease, the changes on CXR associated with TB disease in younger children may be subtle and hard to see if the quality is not optimal. When using CXR for TB screening in children, both posteroanterior and lateral views should be done. Besides cavitary disease, the other most common abnormalities are enlarged hilar lymph nodes, enlarged hilar and paratracheal lymph nodes, enlarged lymph glands compressing the airways, pneumonic consolidation with lymph node enlargement, miliary TB and pleural effusions. It may sometimes be difficult to distinguish abnormally enlarged paratracheal and hilar lymph nodes from the normal vascular structures. These subtle findings on CXR in younger children may affect the sensitivity and specificity of CXR. The help of a practitioner experienced in interpreting paediatric chest radiography may be sought to resolve questions about interpretation. CAD software for interpreting plain CXR for TB is now recommended by WHO as an alternative to human reading (Chapter 4); however, this recommendation is limited to people aged \u2265 15 years, and more data should be collected to validate the performance of CAD for TB in children. ? ?", "Chapter 6. Screening for tuberculosis disease in children 55 CXR can be used in combination with symptom screening (see 6.4 for algorithm options for screening child contacts). CXR is not, however, readily available in many locations, and travel to another location for a CXR may not be feasible for a caregiver, who may be unable to make time or to afford direct or indirect costs for travel, time, support or the radiography service. Mobile CXR units may be used to reach populations that otherwise would be unable to access a health centre with a radiography machine. These, however, require financial and logistical support, and, to be clinically useful, a mobile unit would have to have a regular schedule. CXR emits a small amount of radiation; however, the radiation risk is very low. Chapter 3 outlines additional considerations for implementing CXR, including the benefits and drawbacks of serial and parallel screening when CXR is combined with symptom screening. 6.2.3 WHO-recommended rapid molecular diagnostic tests mWRDs are not currently recommended for screening for TB disease in children < 15 years. 6.2.4 Tests of TB infection As for adults, tuberculin skin tests and interferon-g release assays should not be used to screen for TB disease in children (12, 34), as these tests cannot distinguish TB infection from TB disease and cannot predict who will progress to TB disease. Both tests may be influenced by mechanisms unrelated to TB infection and give false-negative or false-positive results. The role of these tests in decision-making for TPT is discussed elsewhere (4, 5). 6.2.5 Considerations for implementation Contact screening can be difficult. Once the contacts of a TB patient have been identified, they should be screened for TB symptoms and/or undergo CXR, followed by appropriate diagnostic evaluation (4, 5) . T racing of household contacts usually identifies many close contacts who are eligible for screening and TPT; however, it is expensive and time-consuming for health-care workers to identify the contacts of all known TB patients. Additionally, TB is still a highly stigmatized disease in many countries and contexts, and the visit of a health worker to a patient\u2019s home may draw attention to a diagnosis, risking violation of a patient\u2019s right to medical privacy and discrimination against the household. Alternatively, health-care workers can ask patients to bring their contacts, including children, to a health centre for TB screening, although caretakers or parents may not be able to", "bring children in for evaluation, for a variety of reasons, such as financial or time constraints, lack of appreciation of the importance of screening or distrust of health-care services (42). Health-care providers, health-care managers and health programmes should therefore consider the potential preferences and concerns of parents and caregivers and manage them with sensitivity and tact. Like contacts of any age, children and adolescents who are exposed to someone with TB and who are found not to have TB disease should be assessed for TPT as per national guidelines (4, 5). Inability to conduct CXR should not prevent a child from receiving TPT . Health managers should plan for the resources and logistics necessary to deliver screening tests according to the chosen algorithm, to register data on contact-tracing, including the results of screening tests (preferably electronically) and to integrate screening and TPT services. Routine screening of children who access health care is currently not recommended. Children and adolescents < 15 years who access health care represent a much larger population for potential screening than contacts of TB patients, which has important resource implications for scaling up screening, particularly with more expensive screening and diagnostic tools. In addition, the generally low pre-test probability of TB disease in children and the diagnostic pathway that children typically follow when they screen positive, could lead to false-positive diagnoses and inappropriate treatment of large numbers of children.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 56 6.3 Screening children living with HIV Children living with HIV have a high risk of rapid progression to severe disease and death if a diagnosis of TB is missed. A child with HIV infection is 3.5 times more likely to progress to TB disease than a child who is HIV-negative (39). An estimated 16% of paediatric deaths from TB are among HIV-positive children, resulting in 36 000 deaths annually (2). It is for this reason that WHO strongly recommends that children with HIV be screened for TB. 6.3.1 Screening for symptoms and contact Children with HIV who are < 10 years should be screened for TB at every encounter with a health-care worker, with the following screen: cough, fever, poor weight gain or close contact with someone who has TB. The systematic review conducted for the 2021 screening guidelines showed that presence of any one of these conditions has a sensitivity of 61% and a specificity of 94%, and children who are positive on this screen should undergo further diagnostic evaluation for TB disease. Screening for TB can be difficult in a child living with HIV . Even older children, who may otherwise be expected to have more typical \u201cadult-type\u201d TB disease if they are HIV-infected, frequently have extrapulmonary disease and atypical symptoms (43). Health-care workers should maintain strong clinical suspicion of TB in any child with HIV , even in the absence of classical symptoms of TB, especially in areas with a high TB burden. 6.3.2 Other screening tests There are currently inadequate data to extrapolate use of CXR, CRP or mWRDs as screening tests in adults to children < 10 years living with HIV . T ests for TB infection are not useful for TB screening (see also 6.2.4). 6.3.3 Considerations for implementation Children living with HIV should be followed up closely in the health-care system and should be screened for TB at every routine contact with an HIV care provider, at a health facility or in the community. Given the high risk of progression to TB disease and the high mortality rate, screening for symptoms and contact should also be done at every contact with the health-care system, including events such as vaccination days, maternal health appointments, at nutritional screening and at food support programmes. The combined symptom screen has low specificity, which may lead to", "a large number of false-positive screens and unnecessary diagnostic tests or treatment for TB. Nevertheless, given the high mortality due to untreated TB among children living with HIV , the risk of overtreatment is often outweighed by the benefit of TB treatment. Health-care workers should closely monitor therapy and remain vigilant to the possibility of a false-positive TB diagnosis when the symptoms are due to another disease, such as pneumonia. It may be difficult to determine whether a child has close contact with a person with TB, and it is important to take a careful history of the known exposures of the caretaker and the child. Household contacts are often considered, but, particularly in areas with a high TB prevalence, close contact can occur in a variety of community settings, including school, day care and religious gatherings. A study in South Africa indicated that only half of children with TB had a known household contact with TB (44), and even young children had a high risk of being infected in the community, not just from household members with TB. Therefore, a high index of suspicion of TB in young children should be maintained, especially for children with HIV or of unknown HIV status in settings with a high TB prevalence. Children living with HIV who are found not to have TB disease should receive TPT as per WHO guidelines (4, 5). ?", "Chapter 6. Screening for tuberculosis disease in children 57 6.4 Algorithms for screening Screening algorithms for children are listed in Annex 5. Children 0 to < 15 years with a close contact with TB Any of the following screening algorithms can be used: Fig. A.5.1 Screening with symptoms (page 90) Fig. A.5.2 Screening with CXR (page 91) Fig. A.5.3 Parallel screening with symptoms and CXR (page 92) Fig. A.5.4 Sequential positive serial screening with symptoms and CXR (page 93) Fig. A.5.5 Sequential negative serial screening with symptoms and CXR (page 94) Children 0 to < 10 years living with HIV Fig. A.5.6 Screening with symptoms (page 95)", "References 59 References 1. Houben RM, Dodd PJ. The Global Burden of Latent T uberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Med. 2016;13:e1002152. doi: 10.1371/journal.pmed.1002152. 2. Global tuberculosis report 2020. Geneva: World Health Organization; 2020 ( https://apps.who.int/iris/ bitstream/handle/10665/336069/9789240013131-eng.pdf, accessed 19 February 2021). 3. Storla DG, Yimer S, Bjune GA. A systematic review of delay in the diagnosis and treatment of tuberculosis. BMC Public Health. 2008;8:15. doi: 10.1186/1471\u20132458\u20138-15. 4. WHO consolidated guidelines on tuberculosis, Module 1: Prevention \u2013 T uberculosis preventive treatment. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/item/who-consolidated- guidelines-on-tuberculosis-module-1-prevention-tuberculosis-preventive-treatment, accessed 19 February 2021). 5. WHO operational handbook on tuberculosis. Module 1: Prevention \u2013 tuberculosis preventive treatment. Geneva: World Health Organization; 2020 (https://www.who.int/publications/i/item/9789240002906, accessed 26 February 2021). 6. The End TB Strategy. Geneva: World Health Organization,; (http://www.who.int/tb/strategy/en/, accessed February 19, 2021). 7. Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM et al. WHO\u2019s new end TB strategy. Lancet. 2015;385:1799\u2013801. doi: 10.1016/s0140\u20136736(15)60570\u20130. 8. Andermann A, Blancquaert I, Beauchamp S, D\u00e9ry V . Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008;86:317\u20139. doi: 10.2471/ blt.07.050112. 9. Jaramillo J, Y adav R, Herrera R. Why every word counts: towards patient- and people-centered tuberculosis care. Int J T uberc Lung Dis. 2019;23:547\u201351. doi: 10.5588/ijtld.18.0490. 10. Engaging all health care providers in TB control: Guidance on implementing public-private approaches. Geneva: World Health Organization; 2006 (https://apps.who.int/iris/handle/10665/69240, accessed February 26, 2019). 11. Practical approach to lung health (PAL): A primary health care strategy for integrated management of respiratory conditions in people of five years of age and over. Geneva: World Health Organization; 2005 (https://apps.who.int/iris/handle/10665/69035, accessed February 26, 2019). 12. WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection. Geneva: World Health Organization; 2020 ( https://www.who.int/publications/i/item/ who-consolidated-guidelines-on-tuberculosis-module-3-diagnosis---rapid-diagnostics-for-tuberculosis- detection, accessed February 19, 2021). 13. WHO operational handbook on tuberculosis. Module 3: diagnosis \u2013 rapid diagnosis for tuberculosis detection. Geneva: World Health Organization; 2020 ( https://www.who.int/publications/i/item/who- operational-handbook-on-tuberculosis-module-3-diagnosis---rapid-diagnostics-for-tuberculosis-detection, accessed February 26, 2021).", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 60 14. Biermann O, T ran PB, Viney K, Caws M, L\u00f6nnroth K, Sidney Annerstedt K. Active case-finding policy development, implementation and scale-up in high-burden countries: A mixed-methods survey with National T uberculosis Programme managers and document review. PLoS One. 2020;15:e0240696. doi: 10.1371/journal.pone.0240696. 15. T uberculosis prevalence surveys: a handbook. Geneva: World Health Organization; 2011 (https://www.who. int/tb/advisory_bodies/impact_measurement_taskforce/resources_documents/thelimebook/en/, accessed February 26, 2021). 16. Understanding and using tuberculosis data. Geneva: World Health Organization; 2014 (https://www.who. int/tb/publications/understanding_and_using_tb_data/en/, accessed February 26, 2021). 17. Standards and benchmarks for tuberculosis surveillance and vital registration systems. Checklist and user guide. Geneva: World Health Organization; 2014 (https://www.who.int/tb/publications/standardsandbenchmarks/en/, accessed February 26, 2021). 18. Framework for conducting reviews of tuberculosis programmes. Geneva: World Health Organization; 2014 (https://www.who.int/tb/publications/framework-tb-programme-reviews/en/, accessed February 26, 2021). 19. Public-Private Mix for TB Care and Control: a tool for national situation assessment. . Geneva: World Health Organization; 2007 (https://apps.who.int/iris/handle/10665/69723?locale-attribute=de&locale=en, accessed February 26, 2021). 20. ENGAGE-TB: integrating community-based tuberculosis activities into the work of nongovernmental and other civil society organization. Geneva: World Health Organization; 2012 ( https://apps.who.int/iris/ handle/10665/178160, accessed February 26, 2021). 21. T uberculosis patient cost surveys: a handbook. Geneva: World Health Organization; 2017 ( https://www. who.int/tb/publications/patient_cost_surveys/en/, accessed February 26, 2021). 22. Contributing to health system strengthening. Guiding principles for national tuberculosis programmes. Geneva: World Health Organization; 2008 (https://www.who.int/tb/publications/tb-national-policy/en/, accessed February 26, 2021). 23. Assessing tuberculosis under-reporting through inventory studies. Geneva: World Health Organization; 2012 (https://www.who.int/tb/publications/inventory_studies/en/, accessed February 26, 2021). 24. People-centred framework for tuberculosis programme planning and prioritization: user guide. Geneva: World Health Organization; 2019 (https://apps.who.int/iris/handle/10665/329472, accessed February 26, 2021). 25. Biermann O. \u201c A double-edged sword\u201d: The benefits and harms of active tuberculosis case-finding globally, a qualtiative study based on expert interviews. PLoS One 2021. accessed 26. Marks GB, Nguyen NV , Nguyen PTB, Nguyen TA, Nguyen HB, T ran KH et al. Community-wide Screening for T uberculosis in a High-Prevalence Setting. N Engl J Med. 2019;381:1347\u201357. doi: 10.1056/NEJMoa1902129. 27. StopTB Field guide 3: Finding missing people with TB in communities. Geneva: Stop TB Partnership; 2018 (https://stoptb-strategicinitiative.org/elearning/wp-content/uploads/2019/04/STBFG_03.pdf, accessed February 26, 2021). 28. Ethics guidance for the implementation of the End TB Strategy. Geneva: World Health Organization; 2017 (https://www.who.int/tb/publications/2017/ethics-guidance/en/, accessed February 26, 2021). 29. Blok L, Creswell J, Stevens R, Brouwer M, Ramis O, Weil O et al. A pragmatic approach to measuring, monitoring and evaluating interventions for improved tuberculosis case detection. Int Health. 2014;6:181\u2013 8.", "References 61 31. Priority medical devices list for the COVID-19 response and associated technical specifications: interim guidance. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/336745, accessed February 26, 2021). 32. Camelique O, Scholtissen S, Dousset JP , Bonnet M, Bastard M, Hewison C. Mobile community-based active case-finding for tuberculosis among older populations in rural Cambodia. Int J T uberc Lung Dis. 2019;23:1107\u201314. doi: 10.5588/ijtld.18.0611. 33. Chest radiography in tuberculosis detection: summary of current WHO recommendations and guidance on programmatic approaches. Geneva: World Health Organization; 2016 (https://www.who.int/tb/publications/ chest-radiography/en/, accessed February 26, 2021). 34. Use of T uberculosis Interferon-Gamma Release Assays (IGRAs) in Low- and Middle- Income Countries: Policy Statement. Geneva: World Health Organization; 2011 (https://apps.who.int/iris/handle/10665/44759, accessed February 26, 2021). 35. T uberculosis prevalence surveys: a handbook. Geneva: World Health Organization; 2011 (https://www.who. int/tb/advisory_bodies/impact_measurement_taskforce/resources_documents/thelimebook/en/, accessed February 26, 2021). 36. Hamada Y , Lujan J, Schenkel K, Ford N, Getahun H. Sensitivity and specificity of WHO\u2019s recommended four- symptom screening rule for tuberculosis in people living with HIV: a systematic review and meta-analysis. Lancet HIV . 2018;5:e515-e23. doi: 10.1016/s2352\u20133018(18)30137\u20131. 37. Padyana M, Bhat RV , Dinesha M, Nawaz A. HIV-T uberculosis: A Study of Chest X-Ray Patterns in Relation to CD4 Count. N Am J Med Sci. 2012;4:221\u20135. doi: 10.4103/1947\u20132714.95904. 38. Colditz GA, Berkey CS, Mosteller F, Brewer TF, Wilson ME, Burdick E et al. The efficacy of bacillus Calmette- Gu\u00e9rin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics. 1995;96:29\u201335. accessed 39. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. Jama. 1994;271:698\u2013702. accessed 40. Martinez L, Cords O, Horsburgh CR, Andrews JR. The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. Lancet. 2020;395:973\u201384. doi: 10.1016/ s0140\u20136736(20)30166\u20135. 41. Dodd PJ, Yuen CM, Sismanidis C, Seddon JA, Jenkins HE. The global burden of tuberculosis mortality in children: a mathematical modelling study. Lancet Glob Health. 2017;5:e898-e906. doi: 10.1016/ s2214\u2013109x(17)30289\u20139. 42. Marais BJ, Gie RP , Schaaf HS, Hesseling AC, Obihara CC, Starke JJ et al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J T uberc Lung Dis. 2004;8:392\u2013402. accessed 43. Blok L, Sahu S, Creswell J, Alba S, Stevens R, Bakker MI. Comparative meta-analysis of tuberculosis contact investigation interventions in eleven high burden countries.", "PLoS One. 2015;10:e0119822. doi: 10.1371/ journal.pone.0119822. 44. Venturini E, T urkova A, Chiappini E, Galli L, de Martino M, Thorne C. T uberculosis and HIV co-infection in children. BMC Infect Dis. 2014;14 Suppl 1:S5. doi: 10.1186/1471\u20132334\u201314-s1-s5. 45. Schaaf HS, Michaelis IA, Richardson M, Booysen CN, Gie RP , Warren R et al. Adult-to-child transmission of tuberculosis: household or community contact? Int J T uberc Lung Dis. 2003;7:426\u201331.", "Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 63 Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) Illustrations of 10 possible algorithms for screening individuals aged 15 years and older among the general population and high-risk groups where screening is recommended.", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 64 Fig. A.1.1 \u2013 Screening with cough \u2212+ Population ? Negative Screen Evaluate for TPT per eligiblity Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated Prolonged Cough FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 1a #1", "Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 65 Fig. A.1.2 \u2013 Parallel screening with cough and CXR Prolonged Cough CXR \u2212 +\u2212 + ? ? Population Negative Screen Evaluate for TPT per eligiblity Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated if either or both are positive FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 1b #2", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 66 Fig. A.1.3 \u2013 Sequential positive serial screening with cough and CXR Population ? \u2212+ + \u2212 CXR Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated Negative Screen Evaluate for TPT per elegibility Prolonged Cough ? Negative Screen Explore alternate diagnoses Evaluate for TPT per elegibility", "Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 67 Fig. A.1.4 \u2013 Sequential negative serial screening with cough and CXR CXR + \u2212 + \u2212 Prolonged Cough ? ? Population Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated Negative Screen Evaluate for TPT per elegibility FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 1d #4", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 68 Fig. A.1.5 \u2013 Screening with any TB symptom \u2212+ Population ? Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated TB Symptoms Negative Screen Evaluate for TPT per elegibility FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 2a #5", "Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 69 Fig. A.1.6 \u2013 Parallel screening with any TB symptom and CXR TB Symptoms CXR \u2212 +\u2212 + ? Population Negative Screen Evaluate for TPT per elegibility Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated if either or both are positive ? FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 2b #6", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 70 Fig. A.1.7 \u2013 Sequential positive serial screening with any TB symptom and CXR Population CXR ? \u2212+ + \u2212 Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated Negative Screen Evaluate for TPT per elegibility Negative Screen Explore alternate diagnoses Evaluate for TPT per elegibility ? TB Symptoms FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 2c #7", "Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 71 Fig. A.1.8 \u2013 Sequential negative serial screening with any TB symptom and CXR Population CXR + \u2212 + \u2212 ? Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated Negative Screen Evaluate for TPT per eligiblity ? TB Symptoms FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 2d #8", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 72 Fig. A.1.9 \u2013 Screening with CXR Population CXR ? + \u2212 Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated Negative Screen Evaluate for TPT per eligiblity FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 3 #9", "Annex 1 Screening algorithms for the general population and high-risk groups (not including people living with HIV) 73 Fig. A.1.10 \u2013 Screening with mWRD mWRD Population ? Refer for diagnostic evaluation to assess for clinical manifestations of TB disease. Explore alternate diagnoses if pa- tient has been treated for TB in past 5 years. + \u2212 Negative Screen Evaluate for TPT per eligiblity FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms 4 #10", "Annex 2 Comparative performance of algorithms for the general population and high-risk groups (not including people living with HIV) 75 Annex 2 Comparative performance of algorithms for the general population and high-risk groups (not including people living with HIV) The tables below contain modelled estimates of the performance and outcomes of the 10 screening algorithms described above, when applied to a population of 100,000 people being screened, across three different TB prevalence settings: 0.5%, 1% and 2%. 1 \u2013 Screening with cough 2 \u2013 Parallel screening with cough and CXR 3 \u2013 Sequential positive serial screening with cough and CXR 4 \u2013 Sequential negative serial screening with cough and CXR 5 \u2013 Screening with any TB symptom 6 \u2013 Parallel screening with any TB symptom and CXR 7 \u2013 Sequential positive serial screening with any TB symptom and CXR 8 \u2013 Sequential negative serial screening with any TB symptom and CXR 9 \u2013 Screening with CXR followed by mWRD 10 \u2013 Screening with mWRD followed by diagnostic exam (consisting of repeated mWRD, CXR, other clinical tests and procedures as indicated)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 76 Table A.2.1 100 000 people screened with 0.5% TB prevalence (with 500 prevalent TB cases) Algorithm TP FP FN TN % of prevalent cases detected PPV NPV 1 179 113 321 99 387 36% 61.1% 99.7% 2 422 313 78 99 187 84% 57.4% 99.9% 3 170 62 330 99 438 34% 73.4% 99.7% 4 422 313 78 99 187 84% 57.4% 99.9% 5 301 722 199 98 788 60% 29.4% 99.8% 6 424 324 76 99 176 85% 56.7% 99.9% 7 286 392 214 99 108 57% 42.2% 99.8% 8 424 324 76 99 176 85% 56.7% 99.9% 9 402 222 98 99 278 80% 64.4% 99.9% 10 345 527 155 98 973 69% 39.5% 99.8% Table A.2.2 100 000 people screened with 1% TB prevalence (with 1000 prevalent TB cases) Algorithm TP FP FN TN % of prevalent cases detected PPV NPV 1 357 113 643 98 887 36% 76.0% 99.4% 2 843 312 157 98 688 84% 73.0% 99.8% 3 339 61 661 98 939 34% 84.7% 99.3% 4 843 312 157 98 688 84% 73.0% 99.8% 5 602 718 398 98 282 60% 45.6% 99.6% 6 848 322 152 98 678 85% 72.5% 99.8% 7 572 390 428 98 610 57% 59.5% 99.6% 8 848 322 152 98 678 85% 72.5% 99.8% 9 803 221 197 98 779 80% 78.5% 99.8% 10 690 525 310 98 475 69% 56.8% 99.7%", "Annex 2 Comparative performance of algorithms for the general population and high-risk groups (not including people living with HIV) 77 Table A.2.3 100 000 people screened with 2% TB prevalence (with 2000 prevalent TB cases) Algorithm TP FP FN TN % of prevalent cases detected PPV NPV 1 714 112 1286 97 888 36% 86.5% 98.7% 2 1687 308 313 97 692 84% 84.5% 99.7% 3 678 61 1322 97 939 34% 91.8% 98.7% 4 1687 308 313 97 692 84% 84.5% 99.7% 5 1204 711 796 97 289 60% 62.9% 99.2% 6 1696 319 304 97 681 85% 84.2% 99.7% 7 1143 386 857 97 614 57% 74.8% 99.1% 8 1696 319 304 97 681 85% 84.2% 99.7% 9 1607 218 394 97 782 80% 88.0% 99.6% 10 1380 519 620 97 481 69% 72.7% 99.4% TP \u2013 T rue positive diagnosis FP \u2013 False positive diagnosis FN \u2013 False negative diagnosis TN \u2013 T rue negative diagnosis PPV \u2013 Positive predictive value NPV \u2013 Negative predictive value", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 80 Fig. A.3.1 \u2013 W4SS single screening algorithm + \u2212 Negative Screen Assess for TPT W4SS ? PLHIV Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). * PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.1 #11 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "Annex 3 Screening algorithms for adults and adolescents living with HIV 81 Fig. A.3.2 \u2013 CRP single screening algorithm CRP + \u2212 Negative Screen Assess for TPT ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.2 #12 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 82 Fig. A.3.3 \u2013 CXR single screening algorithm + \u2212 Negative Screen Assess for TPT ? CXR PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.3 #13 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "Annex 3 Screening algorithms for adults and adolescents living with HIV 83 Fig. A.3.4 \u2013 Parallel screening algorithm with W4SS and CRP W4SS CRP + \u2212 +\u2212 Negative Screen Assess for TPT if either or both are positive ? ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.4 #14 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 84 Fig. A.3.5 \u2013 Sequential positive screening algorithm with W4SS and CRP CRP W4SS + \u2212 + \u2212 Negative Screen Explore alternate diagnoses Assess for TPT Negative Screen Assess for TPT ? ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.5 #15 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "Annex 3 Screening algorithms for adults and adolescents living with HIV 85 Fig. A.3.6 \u2013 Sequential negative screening algorithm with W4SS and CRP CRP + \u2212 + \u2212 Negative Screen Assess for TPT ? W4SS ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.6 #16 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 86 Fig. A.3.7 \u2013 Parallel screening algorithm with W4SS and CXR CXR W4SS + \u2212 +\u2212 Negative Screen Assess for TPT if either or both are positive ? ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.7 #17 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "Annex 3 Screening algorithms for adults and adolescents living with HIV 87 Fig. A.3.8 \u2013 Sequential positive screening algorithm with W4SS and CXR + \u2212 + \u2212 Negative Screen Explore alternate diagnoses Assess for TPT Negative Screen Assess for TPT W4SS ? CXR ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.8 #18 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 88 Fig. A.3.9 \u2013 Sequential negative screening algorithm with W4SS and CXR + \u2212 + \u2212 Negative Screen Assess for TPT W4SS ? CXR ? PLHIV * Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated See guidelines on TB diagnosis (12). PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.9 #19 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "Annex 3 Screening algorithms for adults and adolescents living with HIV 89 Fig. A.3.10 \u2013 mWRD single screening algorithm for medical inpatients in settings with TB prevalence > 10% Explore alternate diagnoses Assess for TPT if TB disease ruled out mWRD + \u2212 Assess for clinical manifestations of TB disease to confirm diagnosis Explore alternate diagnoses if patient has been treated for TB in past 5 years. See guidelines on TB diagnosis (12). ? PLHIV * PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.10 #20 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 90 Fig. A.3.11 \u2013 mWRD single screening algorithm for people living with HIV PLHIV Negative Screen Assess for TPT Refer for diagnostic evaluation to assess for clinical manifestations of TB disease. Explore alternate diagnoses if patient has been treated for TB in past 5 years. See guidelines on TB diagnosis (12). mWRD ? + \u2212 * PHLIV * UPDATES / 21 JUNE 2021 WHO TB Final Screening Algorithms (DRAFT) A3.11 #21 * In this population, diagnostic testing for TB with LF-LAM and other methods is usually considered early on. See WHO consolidated guidelines on tuberculosis, Module 3: Diagnosis \u2013 Rapid diagnostics for tuberculosis detection (12)", "Annex 4 Comparative performance of algorithms for adults and adolescents living with HIV 91 Annex 4 Comparative performance of algorithms for adults and adolescents living with HIV The tables below contain modelled estimates of the performance and outcomes of the screening algorithms described in Annex 3, when applied to different subpopulations of people living with HIV: outpatients not on ART, outpatients on ART, and inpatients. For each subpopulation, a model is presented of 1,000 persons being screened with a representative TB prevalence. The models were informed by the results of the IPD analysis that was commissioned to evaluate the performance of the W4SS and alternative screening tools in people living with HIV . Table A.4.1 Screening 1000 outpatients living with HIV not enrolled on antiretroviral treatment (ART) with a TB prevalence of 5% Algorithm TP FP FN TN % of prevalent cases detected PPV NPV 1 32 12 19 938 63% 72% 98% 2 33 9 17 941 67% 79% 98% 3 26 7 24 943 53% 78% 98% 4 36 16 14 934 72% 70% 99% 5 29 5 21 945 59% 85% 98% 6 36 16 14 934 72% 70% 99% 7 35 15 15 935 71% 70% 98% 8 24 6 26 944 48% 81% 97% 9 35 15 15 935 71% 70% 98% 11 36 19 14 931 72% 65% 99%", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 92 Table A.4.2 Screening 1000 outpatients living with HIV on antiretroviral treatment (ART) with a TB prevalence of 1% # TP FP FN TN % of prevalent cases detected PPV NPV 1 4 12 6 978 41% 26% 99% 2 3 8 7 982 31% 28% 99% 3 5 15 5 975 54% 27% 100% 4 2 8 8 982 15% 16% 99% 5 1 0 9 990 6% 61% 99% 6 2 8 8 982 15% 16% 99% 7 7 27 3 963 65% 20% 100% 8 4 7 6 983 38% 35% 99% 9 7 27 3 963 65% 20% 100% 11 4 0 6 990 42% 91% 99% Table A.4.3 Screening 1000 inpatients living with HIV with a TB prevalence of 10% Algorithm TP FP FN TN % of prevalent cases detected PPV NPV NNS W4SS followed by mWRD (1) 74 56 26 844 74% 57% 97% 14 mWRD (10) 77 63 23 837 77% 55% 97% 13", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 94 Fig. A.5.1 \u2013 Screening with symptoms Negative Screen Refer for TPT \u2212+ Child Contacts <15y ? TB Symptoms Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms A5.1 #22", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 96 Fig. A.5.3 \u2013 Parallel screening with symptoms and CXR + \u2212 +\u2212 if either or both are positive Negative Screen Refer for TPT Child Contacts <15y ? TB Symptoms ? CXR Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms A5.3 #24", "Annex 5 Screening algorithms for children 97 Fig. A.5.4 \u2013 Sequential positive serial screening with symptoms and CXR \u2212+ + \u2212 Negative Screen Explore alternate diagnoses Refer for TPT ? TB Symptoms Negative Screen Refer for TPT ? CXR Child Contacts <15y Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms A5.4 #25", "WHO operational handbook on tuberculosis: systematic screening for tuberculosis disease 98 Fig. A.5.5 \u2013 Sequential negative serial screening with symptoms and CXR + \u2212 Child Contacts <15y \u2212+ Negative Screen Refer for TPT Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated ? CXR ? TB Symptoms FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms A5.5 #26", "Annex 5 Screening algorithms for children 99 Fig. A.5.6 \u2013 Screening with symptoms (for children living with HIV < 10 years) \u2212+ Children Living with HIV <10y Negative Screen Refer for TPT Refer for diagnostic evaluation including mWRD & clinical evaluation as indicated TB Symptoms ? FINAL TO DESIGNER / 8 MARCH 2021 WHO TB Final Screening Algorithms A5.6 #27", "1.1 PRIMARY TUBERCULOSIS Primary tuberculosis occurs upon initial infection with Mycobacterium tuberculosis. Radiographic findings may include: - Lymphadenopathy: Most common radiological manifestation of primary TB, especially in children (up to 96%). Typically involves right paratracheal, hilar, or subcarinal lymph nodes. Can also be seen in adults (43% of cases). - Parenchymal consolidation: Dense, homogeneous, well-defined consolidation commonly affecting the middle and lower lung zones. Any lobe can be affected. - Ghon focus: A small calcified granulomatous lesion, typically in the periphery of the lung (superior part of lower lobe or inferior part of upper lobe). - Ghon complex: Ghon focus combined with ipsilateral hilar lymph node enlargement. - Ranke complex: Calcified Ghon focus plus calcified hilar lymph nodes, indicating healed primary TB. - Pleural effusion: Common manifestation, particularly in children and young adults. Usually unilateral. More frequent in HIV-positive patients. - Miliary pattern: Fine (1-3mm) nodules diffusely scattered throughout both lungs, indicating hematogenous dissemination. CXR may be normal in 25-40% of early cases. - Normal radiograph: Primary TB can present with a completely normal chest X-ray in many cases, particularly early in infection. 1.2 POST-PRIMARY (REACTIVATION) TUBERCULOSIS Post-primary TB occurs from reactivation of latent infection or reinfection. Classic radiographic findings include: - Upper lobe predominance: Strong predilection for the apical and posterior segments of the upper lobes, and the superior segments of the lower lobes. This distribution is due to higher oxygen tension in these regions favoring mycobacterial growth. - Cavitation: Present in approximately 40-50% of post-primary TB cases. Thick-walled cavities with surrounding consolidation suggest active disease. Air-fluid levels within cavities may indicate superimposed bacterial or fungal infection. Thin-walled cavities may represent healed or chronic disease. - Consolidation: Focal, patchy, or poorly defined opacities, predominantly in the upper lung zones. May be unilateral or bilateral. - Fibronodular opacities: Irregular, patchy opacities with linear densities suggesting fibrosis, typically in the upper lobes. - Tree-in-bud pattern: 2-4mm centrilobular nodules connected to branching linear structures (best seen on CT), highly suggestive of endobronchial spread of TB. - Tuberculoma: Rounded, well-defined nodular lesion, typically 1-3cm in diameter, representing an encapsulated granuloma. May contain central calcification. - Bronchogenic spread: Ill-defined nodular opacities scattered through the lung, resulting from endobronchial dissemination of infected material. 1.3 MILIARY TUBERCULOSIS - Characterized by numerous tiny (1-3mm) nodules uniformly distributed throughout both lungs, representing hematogenous dissemination. - Nodules may be sharply or poorly defined. - CXR may be normal in", "calcification. - Bronchogenic spread: Ill-defined nodular opacities scattered through the lung, resulting from endobronchial dissemination of infected material. 1.3 MILIARY TUBERCULOSIS - Characterized by numerous tiny (1-3mm) nodules uniformly distributed throughout both lungs, representing hematogenous dissemination. - Nodules may be sharply or poorly defined. - CXR may be normal in 25-40% of early cases. - CT is more sensitive than CXR for early detection. - Associated with interstitial septal thickening. - Occurs more frequently in immunocompromised patients. 1.4 TB IN HIV-POSITIVE PATIENTS Radiographic manifestations can be atypical: - Lower and middle lobe involvement more common - Less cavitation - More frequent lymphadenopathy - Miliary pattern more common - Normal CXR more frequent (up to 22%) - Pleural effusion more common - Atypical consolidation patterns", "2.1 WHO RECOMMENDATIONS According to WHO consolidated guidelines on tuberculosis: - CXR is recommended as a screening tool for TB in: * People living with HIV * Close contacts of TB patients * Prisoners and other high-risk populations * Populations with high TB burden - CXR has sensitivity of approximately 87-98% for active pulmonary TB when interpreted by an expert reader. - Specificity ranges from 56-75% depending on the population and reader experience. - CXR should be used in combination with other diagnostic tools for TB confirmation. 2.2 COMPUTER-AIDED DETECTION (CAD) - WHO recommends CAD as an alternative to human interpretation of CXR for TB screening (since 2021 guidelines update). - CAD systems can achieve sensitivity comparable to expert radiologists. - Particularly useful in resource-limited settings with limited access to trained radiologists. - Multiple CAD products have been evaluated and shown high accuracy. 2.3 LIMITATIONS OF CHEST X-RAY FOR TB - Cannot definitively confirm TB (other diseases can mimic TB appearances) - Inter-reader variability is significant (kappa values 0.3-0.6) - Sensitivity decreases in: * Immunocompromised patients (HIV, diabetes) * Early disease * Smear-negative TB * Extrapulmonary TB - Specificity is limited (many conditions can mimic TB) - Normal CXR does not completely exclude pulmonary TB", "Conditions that can mimic tuberculosis on chest X-ray: 3.1 Upper Lobe Lesions: - Sarcoidosis - Fungal infections (histoplasmosis, coccidioidomycosis) - Lung cancer (primary bronchogenic carcinoma) - Pneumoconiosis (silicosis) - Ankylosing spondylitis 3.2 Cavitary Lesions: - Lung abscess - Necrotizing pneumonia - Squamous cell carcinoma - Wegener's granulomatosis - Fungal infections (aspergillosis) 3.3 Miliary Pattern: - Miliary metastases (thyroid, melanoma, renal) - Sarcoidosis - Fungal infections (histoplasmosis) - Pneumoconiosis 3.4 Lymphadenopathy: - Lymphoma - Sarcoidosis - Metastatic disease - Other infections", "4.1 WHEN CXR SUGGESTS TB: Recommended next steps: 1. Sputum smear microscopy (at least 2 specimens) 2. GeneXpert MTB/RIF (rapid molecular test): Can detect TB and rifampicin resistance within 2 hours. Recommended by WHO as initial diagnostic test for presumptive pulmonary TB. 3. Mycobacterial culture (gold standard): Takes 2-8 weeks but provides drug susceptibility testing. 4. Tuberculin skin test (TST) or Interferon-Gamma Release Assay (IGRA): Indicates TB infection (latent or active) but cannot distinguish between them. 4.2 WHEN CXR IS NORMAL BUT CLINICAL SUSPICION EXISTS: - Consider repeat CXR in 2-4 weeks - Perform sputum testing regardless - CT scan if available (more sensitive than CXR) - Consider extrapulmonary TB evaluation 4.3 RISK FACTORS TO CONSIDER: - Close contact with known TB case - HIV infection or other immunosuppression - Recent immigration from high-burden country - History of prior TB - Diabetes mellitus - Malnutrition - Smoking - Chronic kidney disease - Silicosis", "5.1 CXR DURING TREATMENT: - Baseline CXR at diagnosis - Follow-up CXR at 2 months (end of intensive phase) - Final CXR at treatment completion - Improvement should be expected but may be slow - Cavities may persist even after successful treatment - New or worsening findings may indicate treatment failure or drug resistance 5.2 SIGNS OF TREATMENT RESPONSE: - Decrease in size of consolidation - Decrease in cavity size - Clearing of miliary nodules - Reduction in pleural effusion - Resolution of lymphadenopathy 5.3 SIGNS OF TREATMENT FAILURE: - No improvement after 2 months - New cavities or enlarging existing ones - New areas of consolidation - Persistent smear positivity - Consider drug resistance (MDR-TB)", "6.1 CHILDREN: - Primary TB more common than post-primary - Lymphadenopathy is the hallmark finding - Consolidation often in middle/lower lobes - Cavitation less common - Miliary pattern more frequent - Diagnosis more challenging due to lower bacterial load 6.2 ELDERLY: - Can present with atypical patterns - Lower lobe involvement more common - May mimic pneumonia or lung cancer - Cavitation still common 6.3 DIABETIC PATIENTS: - Lower lobe involvement more frequent - Multiple cavities more common - Higher bacterial load typical - Worse treatment outcomes", "7.1 ROLE OF AI/DL MODELS: - Deep learning models can achieve sensitivity >90% and specificity >90% for TB detection on chest X-rays. - Ensemble approaches combining multiple architectures (DenseNet, ResNet, EfficientNet) often outperform single models. - Transfer learning from pre-trained models (ImageNet, CheXpert) significantly improves performance. 7.2 EXPLAINABILITY: - Grad-CAM (Gradient-weighted Class Activation Mapping) can highlight image regions most influential in the model's decision. - Clinical validation: Grad-CAM heatmaps should align with known TB-affected lung regions for model decisions to be clinically trustworthy. - Regions of interest include: * Upper lung zones for post-primary TB * Hilar regions for lymphadenopathy * Diffuse patterns for miliary TB * Lower zones in HIV-positive or atypical presentations 7.3 UNCERTAINTY ESTIMATION: - MC (Monte Carlo) Dropout enables uncertainty quantification in predictions. - High uncertainty flags cases that need expert review. - Uncertainty correlates with: * Ambiguous or borderline findings * Image quality issues * Atypical presentations * Cases at the decision boundary 7.4 CLINICAL DECISION SUPPORT: - AI systems should augment, not replace, clinical judgment. - All positive predictions should be confirmed with microbiological testing. - Negative predictions do not exclude TB, especially in high-risk patients. - Integration with clinical data (symptoms, risk factors, lab results) improves diagnostic accuracy.", "1. WHO. Consolidated guidelines on tuberculosis. Module 2: Screening. 2021. 2. WHO. Chest radiography in tuberculosis detection. 2016. 3. Nachiappan AC, et al. Pulmonary tuberculosis: role of radiology in diagnosis and management. RadioGraphics. 2017;37(1):52-72. 4. Lewinsohn DM, et al. Official ATS/IDSA/CDC Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017. 5. Skoura E, et al. The Diagnostic Deceiver: Radiological Pictorial Review of Tuberculosis. Diagnostics. 2020;10(6):389. 6. Defined WHO. Global tuberculosis report 2024. 7. International Standards for Tuberculosis Care, 3rd Ed. The Union. 2014. 8. Qin ZZ, et al. Using artificial intelligence for TB detection. 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