key: cord-0824574-4a2x2sut
authors: Migliori, G. B.; Wu, S. J.; Matteelli, A.; Zenner, D.; Goletti, D.; Ahmedov, S.; Al-Abri, S.; Allen, D. M.; Balcells, M. E.; Garcia-Basteiro, A. L.; Cambau, E.; Chaisson, R. E.; Chee, C. B. E.; Dalcolmo, M. P.; Denholm, J. T.; Erkens, C.; Esposito, S.; Farnia, P.; Friedland, J. S.; Graham, S.; Hamada, Y.; Harries, A. D.; Kay, A. W.; Kritski, A.; Manga, S.; Marais, B. J.; Menzies, D.; Ng, D.; Petrone, L.; Rendon, A.; Silva, D. R.; Schaaf, H. S.; Skrahina, A.; Sotgiu, G.; Thwaites, G.; Tiberi, S.; Tukvadze, N.; Zellweger, J.-P.; D’Ambrosio, L.; Centis, R.; Ong, C. W. M.
title: Clinical standards for the diagnosis, treatment and prevention of TB infection
date: 2022-03-01
journal: Int J Tuberc Lung Dis
DOI: 10.5588/ijtld.21.0753
sha: b9ed308c4f9455989eeccb5448e302246c793f1b
doc_id: 824574
cord_uid: 4a2x2sut

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT. METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement. RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care. CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

In 2020, the World Health Organization (WHO) estimated that approximately 5.8 million individuals were diagnosed with TB disease, with 1.5 million deaths (including those co-infected with HIV). These numbers may be underreported, as the COVID-19 pandemic has led to an underdiagnosis of TB cases, which will likely lead to increased spread of TB infection (TBI) and disease. 1 It is estimated that one quarter of the global population is infected with Mycobacterium tuberculosis (Mtb). 2 Transmission of Mtb is predominantly through the respiratory route: bacilli generated by infectious individuals when coughing, speaking, singing, sneezing, and even breathing are acquired by contacts who inhale droplet nuclei of 1-5 lm. 3, 4 Mtb infection may be rapidly cleared by the innate immune response, or infection may occur leading to either a TB infection TBI, or to TB disease. 5, 6 An estimated 20-25% of individuals become infected following exposure to Mtb. Among these individuals, the risk of TB disease within the first 5 years is 5-15%. 7 The innate and adaptive immune systems of an infected person control the replication of the pathogen. 8 Different risk/predisposing factors can play a role in Mtb progression, including coinfection with HIV or other pathogens (e.g., measles and possibly SARS-CoV-2), young age, comorbidities (e.g., diabetes mellitus [DM] , renal insufficiency and malignancies), genetic factors (e.g., primary immunodeficiencies), malnutrition, immunosuppression with biological agents (e.g., anti-tumour necrosis factor-a agents), harmful habits (e.g., smoking, substance abuse, harmful use of alcohol) and solid organ and haematological transplantation. 5, [9] [10] [11] [12] The management of TBI is described under Pillar One of the WHO's End TB Strategy (Integrated, patientcentred care and prevention) and is a core intervention in pursuit of TB elimination. [13] [14] [15] Our aim is to define the clinical and public health standards for TBI management.

Standards are different from guidelines, and instead present a widely accepted level of diagnosis and care, for all healthcare providers and clinicians, both public and private, for appropriate management in patients who have, or who are presumed to suffer from, a given disease (or infection). [16] [17] [18] [19] The IJTLD Clinical Standards complement existing WHO or other guidelines and integrate their recommendations to provide a specific clinical focus. The standards are universal principles and might need to be adapted to specific settings and situations for future programmatic implementation due to legal, organisational or economic reasons.

Specific evidence in some areas is still limited (e.g., which diagnostic test to perform before starting TPT, or during TBI treatment monitoring). The clinical standards are based on best available evidence and will be updated to capture new evidence as it accumulates over time. 

This consensus-based document describes the following activities:

1 Identifying the population groups that need to be tested (Standard 1). A universal standard was defined, with special considerations for children and possible adaptation in different settings and situations (for organisational, legal or economic reasons). Priorities for future research in TBI are also discussed.

A panel of global experts was identified to represent the main scientific societies, associations and groups active in the field of TB. Of the 62 experts initially invited, 51 agreed to participate and 11 did not respond after one reminder. The 51 respondents were asked to comment via a Delphi process on an initial draft of 11 standards developed by a core coordination team (composed of eight members). Forty-one experts provided valid answers after one reminder. The final panel included TB clinicians (n ¼ 17), TB public health specialists (n ¼ 15), TB paediatricians (n ¼ 4), microbiologists/biologists (n ¼ 3) and methodologists (n ¼ 2). A 5-point Likert scale was used (5: high agreement; 1: low agreement). At the first Delphi round, agreement was high, with a median value of 4-5 for all standards, except for the public health standard (Standard 8). The agreement (defined as score 3) was over 95% for all standards and 73% for the public health standard. Based on substantial agreement on the Standards and on the document outline, a draft document was jointly developed by the expert panel, reducing the original 11 standards to eight. The document underwent nine rounds of revision and the final version was approved by consensus (100% agreement).

All individuals belonging to at-risk groups for TB should undergo testing for TBI

The WHO outlined the risk/predisposing factors, and the following population groups are at high risk for progression to TB disease or high rates of TBI (Table 1) People with DM, those who engage in the harmful use of alcohol, tobacco smokers and underweight people have a higher risk for TB progression than the general population; however, systematic TBI testing and treatment is not recommended unless they also belong to other risk groups described above (Table  1) . 11, 20, 21 Infection and subsequent reactivation of TBI is a probabilistic phenomenon, involving many different factors. [22] [23] [24] An individual with respiratory TB disease generates infectious droplet nuclei, the number of which depends on the cough strength, presence of lung cavities, sputum viscosity and ventilation. 3, 9 The contact needs to inhale infectious droplet nuclei, each containing at least one inhaled viable and virulent Mtb bacillus (via one or more exposures), which must reach the alveolar macrophages in the lung to become infected. To interrupt this chain of exposure, it is crucial that the source patient receives prompt and effective TB treatment and that appropriate infection control measures are in place. Rigorous monitoring of the different steps in the cascade of care is further elaborated in Standard 8.

All individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session

Individuals who undergo TBI testing should receive TPT if tested positive (i.e., a decision to test should be a decision to treat). Each individual considered for TPT should receive counselling and health education, including a specific session during the follow-up for treatment monitoring, organised according to feasibility and cost-effectiveness criteria, based on the availability of health services and tailored to the individual's needs. Health education is essential for TPT adherence and in ensuring safety; not only does it provide instructions for reporting adverse events but also informs eligible persons on individual risks and benefits, thereby motivating treatment completion. The ease of contact with a healthcare provider would enable the individual to report any adverse effects from drugs used for TPT. 25 Components of education include information on TB, its mode of transmission, prevention, and drugs available to treat both TBI and disease, and on when to contact the healthcare provider in the event of symptoms suggestive of adverse effects, or treatment interruptions. To adequately inform the individual and obtain the individual's consent to TBI management (see also Standard 8) , the difference between TB disease and TBI should be explained, highlighting that effective TPT reduces the risk of progression from TBI to TB disease. To facilitate early recognition of drug adverse effects and reporting to healthcare providers, major adverse effects of the TPT drugs should be explained.

Furthermore, the counselling and education session may be an opportunity to promote other healthy lifestyle behaviours such as good nutrition or smoking cessation, to discuss how to combine treatment intake with daily activities to improve treatment adherence and to highlight or better manage risk factors predisposing to TB disease (e.g., HIV, DM). Health education should also be provided to the exposed families and household members. 26 This is especially important for children, as parents and/or other caregivers will be responsible for administering medication. Health education should be age-specific, gender-sensitive, delivered in the patient's own language and address potential challenges for the caregiver when administering medications. 16, 17 The availability of palatable paediatric formulations and tolerability of medications would help adherence to treatment. Recommendations for an effective health education and counselling session are given in Table 2 .

Testing for TBI: timing and the test of choice should be optimised Standard 1 outlined the population groups that should be carefully evaluated for TBI testing as it identifies individuals who are most likely to benefit from treatment. 20 To date, the skin-based tuberculin skin test (TST) and blood-based interferon c-release assays (IGRAs) are the two test categories widely used as a proxy for TBI diagnosis. These tests identify people who were infected with Mtb in the past or at present by measuring the immune response to the bacilli (Table 3) . However, there is a 6-8-week conversion window for these tests; therefore, a reliable assessment cannot be made within 2 months of the last infectious exposure. Both TST and IGRAs identify individuals who are at risk of progression to TB disease and are equally recommended for TBI testing. 27 Advantages and disadvantages are outlined in Table 3 . The use of IGRAs is recommended for individuals who have been vaccinated with bacilli Calmette-Guérin (BCG) and would therefore crossreact to tuberculin; for those aged 5 years; and in settings where a cold chain cannot be maintained, as reagents for TST are temperature-sensitive. 9, 20, 28 Limitations of TST include the need for two consecutive healthcare visits, the requirement for skilled personnel for TST application and analysis of the result at 48-72 h, and the recommended use of different cut-off points for TST positivity in various target populations, which makes interpretation more complex. However, IGRAs require phlebotomy, which requires a relatively large volume of blood from children, advanced laboratory equipment and technical expertise. Although more expensive than the TST, IGRAs require just one healthcare visit instead of two visits at specified time points, and are not observer-dependent, as these provide an objective result based on an internal control. 9, 20 Newer and cheaper tests for TBI testing are needed to overcome the issues described. Newer skin tests and simplified IGRAs have been developed, but data on their performance are currently limited. 9, 27, 29, 30 There is provisional evidence on the performance of a lateral flow assay, which is a potential point-of-care test (compared to the commercially available IGRAs for both immunocompetent and immunocompromised patients), but it has not yet been endorsed by the WHO. [31] [32] [33] 

TB disease should be excluded prior to the initiation of preventive therapy Existing TPT regimens utilise mono or dual-drug therapy. As a result, it is critical to ensure that TB disease is absent before commencing TPT to avoid undertreating TB disease and to eliminate the possibility of developing drug resistance (which would require treatment with a minimum of three, and preferably four effective WHO-recommended TB drugs). 34 Screening for the four symptoms of cough, fever, weight loss and/or night sweats is the first key step in adults and adolescents, including patients living with HIV/AIDS (PLHA) regardless of antiretroviral treatment (ART) status. 20, 35, 36 For infants and children living with HIV/AIDS and/or in contact with a person with infectious TB disease, screening for poor weight gain (failure to thrive) or weight loss, reduced playfulness or lethargy, fever and active cough is recommended; this is feasible in a contacttracing scenario. 20, 37, 38 Symptom screening and a chest X-ray (CXR) are strongly recommended before commencing TPT. Physical examination should also be conducted to ensure that there are no palpable lymphadenopathy suggestive of TB lymphadenitis or other signs of extrapulmonary TB disease. An evidence-based algorithm to exclude TB disease is shown in Figure 1 . We acknowledge that CXR and the expertise to interpret the CXR may not be readily available, especially in resource-limited settings. In such scenarios, the lack of CXR should not be a barrier to TPT, and symptom screening should be prioritised. 20 Individuals with symptoms suggestive of TB disease should be investigated according to national guidelines, including PLHA with normal CXR, as it is well-recognised that TB disease may still be present. 39 Constitutional symptoms may overlap with other diseases such as malignancies, which may also co-exist with TB disease; further investigations are therefore needed when TB investigations are negative. 40 Those in whom TB disease and other differential diagnoses are excluded should be assessed for eligibility for TPT. The investigations that are used to exclude TB disease are shown in Table 4 . Both CXR and chest computed tomography (CT) scans are well-established clinical tools to investigate TB disease. Computer-assisted diagnostic software such as the computer-aided detection of TBrelated abnormalities on CXR (CAD) combines digital CXR with an algorithmic interpretation to provide a TB risk score; in some cases, this may be complemented by remote expertise in order to diagnose pulmonary TB promptly and select patients who should undergo further TB disease investigations. CAD has now been implemented in resourcelimited settings, where automated interpretation and remote radiology may be particularly helpful. 41 However, this technology is not validated for use in children nor for other pulmonary diseases that mimic TB. Figure 1 Algorithm to exclude TB disease before initiating TPT. *For adults and adolescents, including PLHA, a four-symptom screening of cough, fever, weight loss or night sweats is recommended. For infants and children living with HIV/AIDS and/or in contact with a person with infectious TB disease, screening for poor weight gain/loss of weight, fever, cough, decreased playfulness, symptoms of extrapulmonary TB (e.g., mass in neck, lethargy/sleepiness, vomiting) is recommended. † CXR should be performed but lack of CXR should not be a barrier to initiating TPT in resource-limited settings. ‡ TST or IGRA if available is ideal to identify PLHA who might benefit most from TPT. § Patients should also be investigated for other diseases such as malignancies which have similar constitutional symptoms with TB disease. If clinical suspicion for TB disease is high but investigations are negative, a specialist may be consulted to determine if the patient should be empirically started on anti-TB treatment. In the event that TB disease is excluded, PLHA and household contacts 5 years old should be considered for TST/IGRA screening and TPT. TPT ¼ TB preventive therapy; PLHA ¼ patients living HIV/AIDS; TST ¼ tuberculin skin test; IGRA ¼ interferon-c release assay; CXR ¼ chest X-ray.

Pregnancy is not an absolute contra-indication to CXR. Additional measures, including a lead shield, may be used to protect the foetus with the CXR taken at full-inspiration. In asymptomatic at-risk individuals who test negative for TBI in the first instance, the frequency of symptom screening, TBI testing (TST or IGRA testing) and CXR are dependent on individual risk and would need to be defined by local health authorities. If CXR and/or IGRA/TST testing are unavailable in an asymptomatic individual who is at risk of progressing to TB disease, the WHO recommends that TPT should still be started. 20 A history of treated TB disease or treated TBI are not contraindications to TPT and should be recommended in young children (,5 years of age), PLHA or individuals with silicosis, who may be at high risk of progression to TB disease if re-exposed to infectious TB patients. 42,43

All candidates for TPT should undergo a set of baseline examinations TPT regimens containing rifamycins and/or isoniazid (H, INH) may confer a small risk of hepatoxicity, which is age-related for INH. 44 There is currently no strong evidence on the need for liver function tests at baseline, although this is recommended in many guidelines and protocols. 45 However, individuals in the following categories should be closely monitored for drug-induced liver injury from TPT and undergo baseline liver function tests: history of liver disease, including viral hepatitis; harmful alcohol intake; age .35 years; pregnancy and up to 3 months postpartum; immunocompromised individuals, including PLHA; exposure to statin therapy; and the mentally incapacitated, who are unable to reliably report symptoms of hepatotoxicity (e.g., dementia) ( Table  5) . TPT with rifampicin (R, RIF) and/or INH can be started if liver enzymes are ,3x upper limit of normal. In the context of drug resistance and a TPT with fluoroquinolones in adults, a baseline electrocardiogram (ECG) should be performed to ensure that the QTc interval is not prolonged (relative contraindication). Candidates should be counselled about the risks of tendinopathies in adults, while those with DM should also be informed on the risks of hypoglycaemia which may occur with use of fluoroquinolones.

We recognise that baseline liver function tests, and ECG may not be routinely available in all settings. This should not be a reason to withhold TPT. Counselling individuals should be done regardless of baseline tests, symptoms suggestive of drug-induced liver injury (e.g., new onset nausea and/or vomiting, abdominal pain, jaundice, tea-coloured urine, which should be differentiated from the expected orangecoloured urine if receiving a rifamycin), or palpitations suggestive of arrhythmias if receiving fluoroquinolones. Should abnormalities be found, patients are to be regularly monitored throughout TPT, as described in Standard 7. All patients should be informed of potential serious adverse effects and be instructed to immediately stop TPT and communicate with their healthcare provider should potentially severe adverse effects occur.

Individuals initiating TPT should receive one of the following regimens

The following options are recommended by the WHO for the treatment of drug-susceptible TBI. 20 3 months of daily INH plus RIF (3HR) 4 months of daily RIF alone (4R) 6 months of daily INH (6H) 12 weeks of once-weekly rifapentine (P, RPT) plus INH (3HP) 1 month of daily RPT plus INH (1HP) A regimen of 36 months of daily INH may be given to adults and adolescents living with HIV in settings with very high risk of TB transmission. Also, in selected high-risk household contacts of patients with multidrug-resistant TB (MDR-TB), the following TPT may be considered based on an individualised risk assessment and a sound clinical justification (especially in children less than 5 years of age): 6 months of daily levofloxacin with or without ethambutol or another drug to which the source case's Mtb isolate is susceptible.

TPT for an infection with strains presumed to be drug-susceptible can be broadly categorised into two types: 1) treatment with regimens containing a rifamycin (RIF or RPT) of 1-4 months' duration, or 2) monotherapy with INH for at least 6 months. A summary of the regimen and the evidence for each regimen is presented in Table 6 .

Benefits outweigh potential harms for all recommended regimens. Regimens should be chosen considering the individual's characteristics such as age, risk of toxicity or drug-drug interaction, comorbidities, drug susceptibility of the likely source strain, drug availability and availability of appropriate formulations (i.e., fixed-dose combination [FDC] pills). The choice is also determined by programmatic factors such as the choice to use or not to use rifamycin-containing regimens for prevention. The WHO recommends that national TB programmes should progressively transition to shorter rifamycinbased regimens given the better safety profile and better prospects of TPT completion. 20 3HR is a convenient and safe regimen with a FDC pill(s) and higher rate of completion compared to 6H. 4R is likely to be better tolerated and safer than 3HR or 6H. However, there is concern regarding the use of RIF as a single drug in high-prevalence, low-resource countries, where exclusion of TB disease may be problematic, or in settings where RIF is readily available as an over-the-counter drug without the need for prescriptions from a medical practitioner. In such settings, there may be an increase in RIFresistant TB. The 6H (or 9H) regimen has long been the only available regimen, and is therefore well studied. The reasons to choose this regimen presently are mainly due to fewer drug-drug interactions than rifamycin regimens (especially in PLHA on protease inhibitor-based regimen, nevirapine, or integrase inhibitors due to potential drug-drug interactions), scarcity of alternative regimens, mainly in lowresource countries. The WHO had noted that all regimens can be self-administered, and that directlyobserved-therapy (DOT) would pose a significant barrier to implementation. 20 Individuals should be supported through education and counselling as described in Standard 2.

Newer studies show that RPT-based regimens have better benefit/risk profile than INH monotherapy but its use is restricted by availability. 1HP, the shortest regimen, would offer significant advantages. However, its effectiveness, especially in different populations at risk (e.g., young children), remains to be confirmed by future studies. Its cost and limited availability are a barrier for resource-limited settings. In general, for migrants, the homeless and in current or former prisoners in whom there is limited opportunity for follow-up during treatment, a shorter treatment may be more suitable. Although a systematic review conducted in 2019 did not confirm higher risk for severe adverse effects in pregnant women taking INH, there were two deaths in the INH arm in a large randomised controlled trial (RCT) in HIV pregnant women. 46 INH use in pregnancy may be associated with higher risks of liver failure, and close monitoring is therefore required.

While obtaining baseline liver function tests when INH preventive therapy in pregnancy is strongly encouraged, unavailability of liver function tests should not be a barrier, unless there are other risk factors for liver toxicity. RIF is considered safe in pregnancy. There is limited data on the pharmacokinetics and safety of RPT in pregnancy; therefore, the use of 1HP and 3HP in pregnancy should be avoided until there is more evidence on dosing and safety. Individuals at risk for peripheral neuropathy, such as those with malnutrition, those who engage in harmful use of alcohol, PLHA, those with renal failure or DM, and those pregnant or breastfeeding should receive pyridoxine (vitamin B6) when taking INH-containing regimens. Unavailability of pyridoxine should not be a reason to withhold TPT.

Regimens based on INH and RIF can be used in individuals of all ages. There are no or very limited data on the efficacy and safety of RPT in children aged ,2 years, and both the 1HP and 3HP regimens are only recommended for use in children aged 2 years. 47 In many countries, RPT and child-friendly formulations are not available. Continuous drug supply needs to be guaranteed, as well as an adequate budget for training, dedicated staff and other programmatic needs. FDCs of 3HR, in doses appropriate for children and adults, should be used where possible to reduce the number of tablets to be taken. FDCs of 3HP are expected to be available in the near future, which will facilitate administration. There is no evidence that TPT increases the risk of development of drug resistance, provided that TB disease has been excluded by symptom screening and CXR before the initiation of therapy (inadvertent monotherapy). [48] [49] [50] The WHO has not recommended repeated courses of preventive therapy due to limited evidence. 20 

Individuals who have started TPT should be monitored

Most individuals who receive TPT are healthy, and adverse effects may influence their likelihood of completing it. Risks of drug-related toxicity should therefore be minimised by informing individuals receiving TPT to avoid alcohol and other drugs that interact with TPT. Individuals on TPT should ideally be monitored clinically at regular monthly intervals, either by phone or text messaging or other modalities according to feasibility. For individuals with abnormal baseline test results, sound clinical judgement is required to ensure that the benefit of TPT outweighs the risks, and they should be tested routinely. Access to informed healthcare providers and appropriate laboratory testing should also be performed for patients who become symptomatic while on treatment (e.g., liver function tests for those with symptoms of hepatotoxicity such as nausea, vomiting and jaundice/teacoloured urine). Adverse effects should be closely followed. For example, it is recommended to stop a rifamycin and/or INH-containing regimen when there is an increase in transaminases to 5 times the upper limit of normal or to 3 times with symptoms of hepatotoxicity.

TPT regimens are generally safe and well-tolerated, but adverse effects, including hypersensitivity reactions, have been associated with INH (asymptomatic elevation of serum liver enzymes up to 5 times the upper limit of normal, peripheral neuropathy and hepatotoxicity) and RIF and RPT (flu-like symptoms, cutaneous reactions, hypersensitivity reactions, gastrointestinal intolerance and hepatotoxicity). Although most of these reactions are minor and occur rarely, specific attention should be paid to hepatic dysfunction to prevent drug-induced liver injury (Table 5 ). If liver function tests are unavailable and subjects were to develop nausea, vomiting, jaundice or confusion indicative of hepatitis or acute liver failure, then TPT should be ceased and such persons referred for further assessment immediately. Adverse effects should be monitored according to the WHO framework for monitoring and managing the safety of medicines against TB disease. 51

Monitoring for TB disease All patients receiving TPT should be clinically observed for TB disease while on TPT (history of symptoms, clinical signs), and further investigations done as clinically indicated. In people diagnosed with MDR-TB, strict clinical observation and close monitoring for TB disease based on sound clinical practice and national guidelines is required for at least 2 years after MDR-TB exposure, regardless of whether or not preventive treatment was given. More evidence for the effectiveness and safety of MDR-TB preventive treatment is urgently needed. The issue of the type of TPT for pre-extensively drug-resistant TB (pre-XDR-TB; i.e., fluoroquinolone-resistant MDR-TB) and XDR-TB (i.e., fluoroquinolone plus either bedaquiline-or linezolid-resistant MDR-TB) will be addressed once data are available.

Regular follow-up, ideally at monthly intervals, is required to support and increase adherence; this can be based on digital technology/telehealth. Monitoring adherence to TPT and ensuring its completion will benefit the individual receiving it. A method to record data on the occurrence and management of adverse effects is advised. There is no data on how to handle interruptions to TPT, i.e., how many missed doses can be replaced by prolonging treatment without compromising efficacy. 20 The WHO provides guidance on the management of treatment interruptions and defines treatment completion as 80% of recommended doses in a maximum number of days, which can be used as a guide. 20 Data for management of nonadherence to the shorter 1HP or 3HP regimes are also needed. Given the absence of a reliable test that can ascertain infection clearance, maximising adherence is especially important. Interventions to enhance adherence and completion of treatment should be tailored to the specific needs of risk groups, including migrants, be culturally appropriate and in the language of the individual. A systematic review conducted for the WHO 2015 TBI guidelines provided heterogeneous results for interventions to improve treatment adherence and completion, and the evidence was considered inconclusive. 52 Although evidence is inconclusive, it is recommended to prepare an adherence plan with the individual and discuss this at each healthcare encounter (ideally at monthly follow-ups), especially for children on TPT. The WHO guidelines for the treatment of drugsusceptible TB disease should be taken as a model, using interventions to support adherence, including mobile phone-based support systems and personalised approaches, because they could also be applied to TPT.

The following treatment outcomes should be reported at the end-of-treatment:

Treatment completion -the recommended number of doses that has been successfully administered within the required duration of treatment according to the selected TPT regimen; Failed -development of TB disease any time while on TPT; Died -death for any reason while on TPT; Lost to follow-up -TPT interrupted by the person for 8 consecutive weeks for 6H, 4 consecutive weeks for 3HP, 3HR and 4R, and 10 consecutive days for 1HP; TPT discontinuation due to toxicity -by clinician due to adverse effects or drug-drug interactions, with or without restart or switching of regimen; Not evaluated -such as records lost, transfer to another health facility with no record of TPT completion.

On completion of treatment, all persons (including those in HIV programmes) should receive a certificate for completion of a TPT regimen. In low-incidence countries, the certificate would prevent people from unnecessary retreatment when attending unlinked medical services. This is particularly relevant for lowincidence countries where reinfections are uncommon. An electronic application for mobile phones has been created by the WHO to guide national programmes on critical data to collect along the TBI care pathway as an accessory to monitoring and evaluation. 53 The feasibility of measuring efficacy of preventive therapy should be assessed. This would require the collection of information about the occurrence of TB disease in people who have received TPT. Measurement of efficacy also requires patients registered for TB treatment to be asked about their history of starting or completing TPT, and updating TBI registers with pre-existing data or the crosslinking of registers (e.g., TBI registers compared with TB treatment or mortality registers). For people who develop TB disease after, or well into a TPT course, drug susceptibility testing is critically important. National surveillance systems for anti-TB drug resistance to drugs used for TPT may need to be strengthened in countries scaling up programmatic management of TB preventive therapy (PMTPT).

A TBI screening and testing register should be kept to inform the cascade of care TBI testing and treatment is recommended by the WHO as a core intervention for TB elimination. 13, 14, 20, 54 Monitoring and evaluation of activities for TPT and for TB screening should be aligned to promote synergies and limit duplication. In addition, barriers to healthcare, especially for migrants where health facilities may not be accessed, should be removed. 55 The implementation of a TBI register, including specific key variables, is essential to describe, measure and evaluate the cascade of care ( Figure 2 ). Programmatic implementation and scaleup of TPT requires strengthening of each step in the cascade of care, starting from the identification of the target population to the completion of TPT. The TBI register represents a best-practice standard for patient follow-up, and programmatic planning; it is also an audit trail for clinical governance to evaluate programmatic effectiveness of the intervention. 20, 56, 57 The register will ensure that individual patients receive appropriate follow-up; clinical management of patients is also useful for programmatic reasons to avoid duplication of notifications, inform the public health response and determine the direction of the programme (including change of target groups or specific support interventions to improve uptake or completion). 58 Individual data are pre- Clinical standards for TB infection ferred over aggregated data, but this depends on local arrangements.

Elements of the TBI register is shown in Figure 3 . Data protection laws and other restrictions at the country or regional level may limit the type of data that can be collected and may necessitate amending modalities of data collection. Here, we outline the components of such a TBI register. Ideally, the individual's consent is taken at the beginning of the screening process, with opt-out consent the preferred option. Outcomes should be carefully recorded, including adverse effects and the occurrence of TB disease. Systems should be in place to ensure TB status can be updated in the register, even after follow-up or successful completion of TBI therapy. Effective implementation of the TBI register allows continuous monitoring of activities and can help programme managers to assess the performance of the TPT components.

The WHO recommends three main indicators for global evaluation of TPT activities (Table 7) : 20 1 Contact investigation coverage: percentage of contacts of bacteriologically confirmed TB patients who were evaluated for TB disease and TBI out of those eligible; 2 TPT coverage: percentage of individuals that initiated on TPT out of those eligible; 3 TPT completion: percentage of individuals completing TPT out of those initiating treatment.

An example of a recording and reporting form is presented in Supplementary Table S1 .

Significant improvement to the current diagnostic and treatment programmes will be necessary for effective widespread implementation. Areas where research gaps have been clearly identified by the scientific community are listed below. 59 Target populations People included in target populations for PMTPT recommended by the WHO only represent a small fraction of the estimated one quarter of the world's population with TBI. Expanding testing and treatment activities to additional target populations will be essential to increase the impact of the intervention and strengthen its contribution to the TB elimination strategy. Quality evidence from clinical trials is lacking for indigenous populations, people with DM, those with harmful use of alcohol, tobacco smokers, the underweight, and those exposed to silica, on steroid treatment, with rheumatological diseases or with cancer. Both direct measurement of the incidence of TB disease and methods for measuring the risk for TB disease should be explored, such as the evaluation of human RNA transcripts (correlate of risk) to investigate the risk of TB reactivation. [60] [61] [62] Improved diagnostic tests and performance of TBI tests in at-risk populations Diagnostic tests with improved performance and predictive value for progression to TB disease are critically needed. The performance of TBI tests should be evaluated in various risk groups to understand how available tools should be optimally used in each population (e.g., combined or sequential use of TST and IGRA). Diagnostic tests for reinfections in treated patients would be highly desirable in high-transmission settings.

Ruling out TB disease This step of the cascade is particularly weak in resource-constrained settings. Operational and clinical studies should be conducted on new reliable and affordable techniques that can reduce health system and patient barriers (e.g., use of mobile chest radiography; computer-assisted radiography reading; C-reactive protein levels). 63 Reliable human RNA transcripts (correlate of risk) that can predict progression to TB disease are urgently needed.

Research to find shorter, better-tolerated TPT regimens than those currently recommended remains a priority, including treatment options after exposure to drug-resistant TB patients as given in Table 8 . More evidence on the ultra-short 1-month regimen of RPT and INH is required, particularly in HIVnegative adults, injection drug users on methadone therapy, children aged ,2 years and in pregnant women. A direct comparison of 1HP vs. 3HP for safety, effectiveness and cost-effectiveness will be useful. Pharmacokinetics studies to establish interactions with newer HIV drugs are required. In addition, the durability of protection of different TPT regimens, including those containing long-acting injectables, need to be evaluated in settings in which TB is highly incident, including the efficacy of repeated courses of TPT. Studies on the preference of different stakeholders for different regimen characteristics would be helpful.

Carefully designed studies, including RCTs, are required to generate evidence on the effectiveness and quality-of-life impact of context-specific interventions to enhance adherence and completion of treatment in specific risk groups. Integration of PMTPT into other health care services (i.e. for PLHA, people with DM, people on immunosuppressive therapy) should be explored. Prospective RCTs are required to determine the incremental benefits of routine monitoring of liver enzyme levels over education and clinical observation alone for preventing severe clinical adverse events, with stratification of the evidence by at-risk population. Use of digital technologies to improve adherence should be carefully explored, including the use of mobile texting for asymptomatic individuals. The same technologies should be applied to treatment completion monitoring.

Although there are some studies comparing 3HP vs. 6H, a comprehensive appraisal of the cost-effectiveness of TBI management stratified by population group, and type of regimen or intervention is warranted. Cost-effectiveness analysis using parameters from different resource settings could allow better planning for the extension of a PMTPT strategy at a national or local level.

The current WHO recommendation on MDR-TB preventive treatment responds to an urgent need from the countries but is based on very weak evidence. The results of currently ongoing RCTs, including those listed in Table 8 , will need to be translated into a policy update as soon as possible. The need, effectiveness and safety of TPT for contacts of people with MDR-TB, pre-XDR-TB and XDR-TB should be evaluated under operational conditions.

Implementation research on context-specific barriers and facilitators is needed for different TBI regimens to explore dimensions such as acceptability, feasibility, equity and resource use. Research is also needed on service delivery models to improve management. Household implementation models could increase the effectiveness and efficiency of delivery of interventions. 64, 65 Future trial evidence could guide how to optimise contact-tracing strategies in households and other congregated settings where transmission may occur, such as the workplace, schools and penitentiary institutions. 

29 S. Manga, 30 B

40 G. Sotgiu, 41 G. Thwaites

Respiratory Diseases Clinical Epidemiology Unit

The global prevalence of latent tuberculosis: a systematic review and meta-analysis

Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe

Capture and visualization of live Mycobacterium tuberculosis bacilli from tuberculosis patient bioaerosols

Essential tuberculosis

Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review

Risk of active tuberculosis in the five years following infection . . . 15%?

Prognostic value of interferon-c release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study

The definition of tuberculosis infection based on the spectrum of tuberculosis disease

Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs

The risk of tuberculosis in children after close exposure: a systematic review and individual-participant metaanalysis

Tuberculosis and COVID-19 co-infection: description of the global cohort

Towards tuberculosis elimination: an action framework for low-incidence countries

Tuberculosis elimination: where are we now?

World Health Organization. The End TB Strategy

International standards for tuberculosis care. 3 rd ed. The Hague, The Netherlands: TB CARE I

ERS/ECDC Statement: European Union Standards for Tuberculosis Care, 2017 update

Clinical standards for the assessment, management and rehabilitation of post-TB lung disease

Launch of the IJTLD Clinical Standards for Lung Health

World Health Organization. WHO operational handbook on tuberculosis: Module 1: Prevention: tuberculosis preventive treatment

Absolute risk of tuberculosis among untreated populations with a positive tuberculin skin test or interferon-gamma release assay result: systematic review and meta-analysis

Guiding principles to reduce tuberculosis transmission in the WHO European Region

Epidemiologic basis of tuberculosis control. 1 st ed

World Health Organization. Guidelines for treatment of drugsusceptible tuberculosis and patient care

Clinical care for patients with post-TB lung disease

Making IGRA testing easier: first performance report of QIAreach QFT for tuberculosis infection diagnosis

Interferon-c release assay performance for tuberculosis in childhood

Tests for tuberculosis infection: landscape analysis

Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon c release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial

First clinical evaluation of the QIAreach(TM) QuantiFERON-TB for tuberculosis infection and active pulmonary disease

Evaluation of QFT-Plus performance using blood samples stored at room temperature

QIAreach QuantiFERON-TB for the diagnosis of M. tuberculosis infection

World Health Organization. Guidelines for treatment of drugsusceptible tuberculosis and patient care

Development of a standardized screening rule for tuberculosis in people living with HIV in resourceconstrained settings: individual participant data meta-analysis of observational studies

Sensitivity and specificity of WHO's recommended four-symptom screening rule for tuberculosis in people living with HIV: a systematic review and meta-analysis

World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children

Symptom-based screening of child tuberculosis contacts: improved feasibility in resource-limited settings

Lack of latent tuberculosis screening and delay in Anti-Retroviral Therapy initiation in HIV-TB coinfection: a 11-year study in an intermediate TB-burden country

Childhood Cancers Misdiagnosed as Tuberculosis in a High Tuberculosis Burden Setting

An evaluation of automated chest radiography reading software for tuberculosis screening among public-and private-sector patients

Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicentre, prospective cohort study

Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis

Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic

Monitoring toxicity in individuals receiving treatment for latent tuberculosis infection: a systematic review versus expert opinion

Isoniazid preventive therapy in HIV-infected pregnant and postpartum women

Safety and feasibility of 1 month of daily rifapentine plus isoniazid to prevent tuberculosis in children and adolescents: a prospective cohort study

49 den Boon S, Matteelli A, Getahun H. Rifampicin resistance after treatment for latent tuberculous infection: a systematic review and meta-analysis

Annual tuberculosis preventive therapy for persons with HIV infection : a randomized trial

Active tuberculosis drug-safety monitoring and management (aDSM): Framework for implementation

World Health Organization. Guidelines on the management of latent tuberculosis infection

World Health Organization. LTBI care: a mobile app to support programmatic management of LTBI

Tuberculosis elimination in the WHO European Region: review of key actions, with a special focus on management of tuberculosis infection

How effective are approaches to migrant screening for infectious diseases in Europe? A systematic review

The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and metaanalysis

Effectiveness of interventions for reducing TB incidence in countries with low TB incidence: a systematic review of reviews

TB contact tracing for young children: an Australian cascade of care review

Interventions to reduce losses in the cascade of care for latent tuberculosis: a systematic review and metaanalysis

Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial

Transcriptional biomarkers for predicting development of TB: progress and clinical considerations

Acute phase proteins and IP-10 as triage tests for the diagnosis of tuberculosis: systematic review and metaanalysis

A blood RNA signature for tuberculosis disease risk: a prospective cohort study

Vikela Ekhaya: a novel, community-based, tuberculosis contact management program in a high burden setting

Tuberculosis preventive therapy for individuals exposed to drug-resistant tuberculosis: feasibility and safety of a community-based delivery of fluoroquinolonecontaining preventive regimen

Interferon-c release assays or tuberculin skin test for detection and management of latent tuberculosis infection: a systematic review and meta-analysis

Treatment of latent tuberculosis infection: an updated network meta-analysis

The effectiveness of a 9-month regimen of isoniazid alone versus 3-and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study

Four months of rifampin or nine months of isoniazid for latent tuberculosis in adults

Safety and side effects of rifampin versus isoniazid in children

Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons

Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid

New regimens to prevent tuberculosis in adults with HIV infection

Three months of rifapentine and isoniazid for latent tuberculosis infection

One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis

Treatment of latent tuberculosis infection in HIV infected persons

How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults?

Continuous isoniazid for the treatment of latent tuberculosis infection in people living with HIV

Treatment for LTBI in contacts of MDR-TB patients, Federated States of Micronesia

Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up