Childhood Tuberculosis (TB) is a staggering problem. In India, approximately 3.42 lakh children (0-14 years of age) are estimated to get TB every year, accounting for about 6% of total TB cases reported to NTEP in 2020[1]. In 2020, approximately one lakh children with TB (0 to 14 years of age) were reported to the NTEP, while an additional 1.4 lakh children were reported to the NTEP in the age group of 15-18 years[2]. Consistently, children constitute 6-7% of all the patients treated under NTEP annually. Nevertheless, there are some variations in the case reporting across the states, attributed to differences in the burden of disease, health-seeking behaviour, and availability of services.

Nearly a third of the children with TB globally are from India, despite an estimated detection gap of about 56%. Children up to the age of 14 years constitute 35% of the population in our country and are estimated to contribute approximately 10% of the caseload. However, reported numbers may be low as many children are treated outside the National TB programme. Pulmonary TB is the most common form of TB in children; however, extra-pulmonary TB (EPTB) in children forms a more significant proportion of cases than adults. Adults comprise the largest proportion of TB cases as the adulthood span is far longer than paediatric. In addition, TB control does not figure prominently as one of the child survival strategies. The child survival strategies are expectedly focused on the diseases with the highest mortality among the under-five, including premature birth, perinatal asphyxia and injuries, pneumonia and diarrhoea. Among the other causes of childhood, mortality is TB, albeit unrecognised yet important. However, the exact contribution of TB to ‘Under-5 Mortality’ is unknown. Many TB related deaths are possibly reported as pneumonia due to similar respiratory symptoms, and autopsy studies from few African nations support this contention. As a singular organism, Mycobacterium tuberculosis (M.tb) contributes to most death of under-five among the world’s middle and lower-income countries.

               Although the principles of diagnosis and treatment remain similar in children and adults, the differences in the type of disease and specific host characteristics bring up some challenging variations. Adults and older children more often have the infectious form of TB, which may be confirmed by testing sputum, while in general, younger children have forms of TB that show up poorly on sputum smears. Moreover, difficulties in accessing the specimen from children who swallow rather than bring out sputum add further challenge. Whereas alternative methods to collect respiratory samples are more invasive and require professional skills. Confirmation of TB and its drug sensitivity does require microbiological testing but the sophistication of diagnosis among children often makes it challenging to decentralise it to the community level.

Rapid molecular diagnostic methods like newer generation cartridge-based nucleic acid amplification tests (Xpert-RifTM /TruenatTM) and Line Probe Assays (LPA) have been approved and employed by the National TB elimination Program (NTEP). These tests can rapidly identify Mycobacterium tuberculosis with much-improved sensitivity compared to conventional smear testing, even among specimens from children but are far more expensive when pursued in the private sector. Nevertheless, the final yield of TB testing is better if the microbiological confirmation is done on good quality specimens from cases with high suspicion of TB based on clinical and radiological abnormalities. As the symptoms suggestive of pulmonary TB are non-specific and overlapping, initial screening with chest imaging helps prioritise cases for testing by NAAT. 

Furthermore, newer molecular tests can simultaneously detect much critical rifampicin resistance as they are nested or two-step automated Polymerase Chain Reaction (PCR), leading to a significant shift in diagnostic strategy. Such diagnostic modalities have paved ways for Universal drug sensitivity testing (U-DST), the core programmatic strategy and refers to upfront testing of all TB cases for Rifampicin resistance and further for Fluoroquinolones and Isoniazid (INH). Therefore, all TB cases (new or retreatment) must now be tested for drug resistance upfront and instituted specific treatment as per the resistance pattern detected.

In addition, several changes have come up in the treatment of TB. Firstly, for children, dosages of anti TB drugs have been revised upwardly to achieve optimal drug levels, and now the Fixed Drug Combinations (FDCs) are used to decrease the risk of missing a particular drug from the prescribed regimen. Secondly, awareness about high initial Isoniazid resistance and its contribution to the failure of the retreatment regimen has led to the use of a third companion drug (Ethambutol) in the continuation phase of the first-line therapy. Lastly, the standard retreatment regimen, commonly known as category II therapy, has been withdrawn.

The current decade has witnessed a revitalisation in new activities led by recent innovations in TB with a renewed commitment to eliminate the disease from the world.  Understanding the disease, drug therapy and its pharmacokinetics, resistance amplification, and newer diagnostics and drugs have created an opportunity to use this knowledge to improve child TB care in specific and child health care in particular. The present updated guidelines capture the use of newer diagnostics and therapy modifications for managing TB in children to achieve the goal of early diagnosis, prompt and effective therapy guided by the sensitivity pattern to key drugs.

 

[1] Central TB Division, 2020. India TB Report - 2020. National Tuberculosis Elimination Program - Annual Report. New Delhi: Central TB Division, Ministry of Health and Family Welfare, Government of India.

[2] Central TB Division, 2021, Nikshay Data from National Tuberculosis Elimination Program, Ministry of Health and Family Welfare, Government of India.

2.1 Presumptive Paediatric TB 

Presumptive Paediatric TB refers to children suspected to be suffering from TB based on any of the following symptoms: persistent fever, cough for more than two weeks, loss of weight. A definite weight loss (>5% loss in the past three months) or failure to gain weight in the past three months despite adequate nutrition with no other apparent cause should prompt detailed history, examination and investigation, including investigations for TB. 

Moreover, presumptive TB cases (Pulmonary or Extrapulmonary) would often have known contact with an infectious TB patient. In a symptomatic child, contact with a person with any form of active TB within the last two years may be deemed significant.

The diagnostic algorithm below gives the recommended pathway for the diagnosis of intrathoracic tuberculosis in children. Experts believe that while the symptoms suggestive of TB can be mimicked by several other diseases; however, if they are properly characterised, the probability of finding those with TB improves. Persistent cough and fever for two weeks or more without a known cause is an excellent clinical marker, particularly if associated with weight loss or a history of exposure to a case of active TB. Weight loss or not gaining weight should always be documented with appropriate and proper weighing. The patient should always be weighed with minimal clothing and without shoes using a tared scale.

All these presumed cases are subjected to further investigation for TB. The initial specific investigation recommended is a frontal Chest skiagram. If a recent good quality chest x-ray film is available, repeat testing is not routinely recommended. This is a significant shift from the earlier guidelines where a sputum smear examination was the initial recommended test.

 

    

Figure. 1 Diagnostic Algorithm for Pulmonary TB in Children

 

2.2. Chest Imaging for Tuberculosis in Children

A plain radiograph with a frontal view of the chest is the initial investigation advised. Radiological findings considered highly suggestive of tuberculosis in the suggested clinical setting include a) miliary shadows – diffuse micronodular shadows affecting both the lungs like a snowstorm. b) intrathoracic lymphadenopathy (usually seen as a dense well-circumscribed ellipsoid or rounded shadows in the hilar or mediastinal regions), c) Chronic fibro-cavitary shadows (usually, but not exclusively, seen in the apical regions).

Findings like consolidations, in-homogenous shadows or bronchopneumonia, etc. are considered non-specific as they may also be seen in other bacterial diseases. The following set of chest skiagrams show the various highly suggestive lesions seen on chest imaging in TB.

 

 

 

 

Figure 2a. Chest Imaging in TB

 

 

Figure 2b. Chest Imaging in TB

 

Chest radiography is also an important tool to support the diagnosis of pulmonary TB in children. In the relevant clinical setting, a diagnosis of TB may need to be made on a clinical basis based on highly suggestive imaging findings of tuberculosis (miliary pattern, hilar or paratracheal lymphadenopathy with or without parenchymal involvement and fibro-cavitary lesions). It is worth remembering that all these imaging patterns also have other differential diagnoses. All presumptive TB cases with these radiological patterns are considered to be probable cases and should be subjected to microbiology to confirm the diagnosis. If microbiological investigations are negative, these children can be deemed to be cases of clinically diagnosed tuberculosis (TB), provided alternative causes are ruled out. Specificity of diagnosis in such situations increases in the presence of pointers like positive TST or history of contact.  

Non-specific findings on chest X-ray refer to patterns other than highly suggestive patterns described above and includes: consolidations, in-homogenous shadows or bronchopneumonia, etc. As these abnormalities can often be seen with other aetiologies like bacterial disease, such patients should be given a course of appropriate antibiotics (Amoxycillin or co-amoxiclav), mainly if the blood counts show neutrophilia.  

Antibiotics like Linezolid or any quinolone should not be used as they have anti-TB action. Clinical clues may prompt earlier investigation for TB in some cases, e.g. widespread bacterial pneumonia is unlikely to be clinically silent (absence of significant distress or fever). In contrast, mycobacterial pneumonia may have disproportionately lesser clinical findings than the extent of radiological changes.

 

 

 

 

 

Figure 2c. Chest Imaging in TB

 

 

 

Suppose the non-specific radiological patterns do not resolve despite adequate antibiotic therapy in a symptomatic child. In that case, they need to be evaluated with Induced Sputum (IS)/ Gastric Aspirate (GA) for M.tb . If negative by NAAT or culture, a further evaluation like CT chest and flexible bronchoscopy for persistent pneumonia are required. The differential diagnosis in such situations is significant, of which TB might be one of the possibilities. These children need to be referred for further evaluation, and a trial of Anti-Tubercular Treatment (ATT) is not justified without ruling out other diseases.

Chest radiographs in a patient who has been treated in the past can have post-TB changes like opacities secondary to pleural thickening, fibro-atelectatic changes or areas of bronchiectasis. These children are usually asymptomatic except in children with post-TB bronchiectasis, where they may show symptoms of suppurative lung disease. Such cases also need expert evaluation to differentiate and confirm disease recurrence if new symptoms come up after successful treatment.   

It is crucial to remember that several factors can lead to both under and overdiagnosis of TB on chest radiology. Leading issues associated with possible errors include technical quality of films like exposure, rotation, motion blur, etc.; inter and intra-individual variations in reading; errors in interpretation due to artefacts; confounders like a thymic shadow, etc.

CT Scan is sometimes necessary but is costly and gives significant radiation. Therefore, it should be used judicially; however, CT is an essential tool for evaluating children with persistent pneumonia or persistent fever without apparent focus. Certain CT patterns that can be highly suggestive of TB, although not diagnostic, are necrotic mediastinal lymphadenopathy, centrilobular nodules with tree-in-bud pattern and cavities with surrounding consolidations. Chest CT scan also may offer an opportunity for CT guided biopsy for tissue diagnosis.

Ultrasonography (USG) of the chest is helpful to assess the pleural fluid collection. It is useful for differentiating thymus and anterior lymph nodes and identifying the best spot for aspiration/ Fine Needle Aspiration Cytology / biopsy in a peripheral lesion.

 

2.3. Microbiological Tests

The new strategy is to test all TB patients upfront for resistance, particularly rifampicin using NTEP-approved rapid NAAT on relevant body specimens. For pulmonary TB, respiratory secretions like self-expectorated sputum or induced sputum or gastric aspirate or lavage, etc., can be used. As the access to samples among children is not easy, there is merit in targeting collection among children after a positive screening on chest radiography. While the patient is immediately subjected to relevant specimen collection and testing if the screening chest imaging shows highly suggestive radiological features, but in case the screening radiograph shows non-specific findings (described before), the respiratory specimen collection for M. tb is advised if the symptom persists even after a full seven days’ course of a potent suitable antibiotic (like Amoxycillin or Co-amoxiclav). Exceptions may need to be made if there is a clinical urgency and the child has a high probability of having tuberculosis.

As most young children cannot expectorate sputum, alternatively, the swallowed sputum is collected from the stomach after a period of fasting (usually 4-6 hrs, preferably overnight) as gastric aspirate. Early morning gastric aspirate is a preferred specimen for most young children with presumptive TB. It needs to be done on an empty stomach and requires skilled staff. While it should ideally be done early in the morning, after overnight fasting (usually feasible in an inpatient), but as an alternative, it can also be collected in ambulatory settings after 4-6 hours of fasting with some compromise on the yield. (See Annexure 2 for Method to collect gastric aspirate; video available at: https://tbcindia.gov.in/index1.php?lang=1&level=2&sublinkid=5305&lid=3415 )

Induced sputum is another sample that can be obtained in children who are unable to produce sputum. Induction of sputum can be easily performed in young children, including infants with an acceptable yield of the sample. It does not require prolonged fasting and should be done with adequate infection control practices as the procedure provokes cough, increasing the risk of transmission. (See Annexure 3 for Method to collect induced sputum; Video available at: https://tbcindia.gov.in/index1.php?lang=1&level=2&sublinkid=5305&lid=3415 ).

A good sputum sample consists of recently discharged material from deep inside the chest (the inner airways) with a minimum amount of oral or nasopharyngeal material, has mucoid or mucopurulent character and should be 2-5 ml in volume. It should be collected in a sterile container after rinsing the oral cavity with clean water. Under the programmatic conditions, a conical tube, like Falcon’s tube, is the preferred container. The collected specimens should be labelled appropriately, safely packaged and transported to the laboratory as soon as possible after collection. If a delay is unavoidable, the samples can be refrigerated to inhibit the growth of unwanted microorganisms and tested no later than seven days after collection. If the patient does not produce any sputum, even after induction, any other available respiratory specimen like bronchoalveolar lavage (BAL), lung aspirate, etc., can be collected by a skilled health care provider depending upon available facilities.

Bronchoscopy and bronchoalveolar lavage are required in select cases of persistent pneumonia for final diagnosis. They may be performed when routine investigations for TB are inconclusive or for children who are drug-resistant TB suspects. Precious or challenging to get specimens like BAL or lung aspirate should also be subjected to culture and drug sensitivity, particularly if the rapid test is negative.

Many children with TB may have a concomitant extra-pulmonary (EP) disease. Specimens from the EP site can also be used to establish a diagnosis. However, no preservative should be used for any extra-pulmonary sample for culture. Moreover, necessary instructions are to be given to the concerned staff for sending the biopsy specimen in normal saline for culture and not in preservatives like formaldehyde as it kills bacilli.

The available initial diagnostic tests are NTEP approved rapid NAAT (Xpert Rif™ - a cartridge-based nested NAAT for detecting M.tb and its resistance to Rifampicin; Truenat™ M.tb  Plus – a chip-based NAAT to detect M.tb and then sequentially test for Rifampicin resistance using M.tb  Rif Dx™). These rapid NAATs can test several different types of clinical specimens like sputum, induced sputum, gastric aspirate or lavage, and various other body fluids. In addition, line probe assays (LPA) are also available under the programme (Hain test/ MTB DRplus™, MTB DRsl™). These tests take up to 72 hours and can be used only on smear-positive sputum specimens or culture isolates for Genotypic DST. This is currently the only WHO, and NTEP recommended rapid test to detect additional drug resistance in MDR-TB and XDR-TB patients. The First Line- LPA thus detects M.tb and the presence of resistance to R and H (MTB DRplus™). A second Line-LPA (MTB DRsl™) is available for testing for resistance to class Fluoroquinolones (FQ) and class second-line injectables (SLI).

A single good quality specimen with the newer rapid molecular tests is usually adequate (unlike two samples needed for the Acid Fast Bacilli smear test). Despite the more recent rapid tests having a much higher sensitivity and specificity than the smear for Acid Fast Bacilli (AFB), the newer tests perform poorly in culture-negative cases. Their sensitivity is less than the culture, which detects between a third to nearly half the cases. Thus, more recent molecular tests are good “Rule–in tests” due to their high specificity. Still, a negative test does not rule out TB disease as approximately half of the paediatric TB cases are culture negative due to the very nature of the disease.

Moreover, studies have shown that newer rapid NAAT tests perform very poorly with pleural or ascitic fluid compared to respiratory specimens, Lymph Node (LN) aspirates, pus and CSF. It is suggested that children with persistent symptoms, non-specific shadows, and negative results of smears and other NAAT samples (GA/IS) should undergo further workup to diagnose persistent pneumonia at appropriate facilities. Many such cases are diagnosed as TB based on the clinical and radiological features after excluding other diagnoses.

As discussed previously, NAAT being a nested PCR, provides additional information about Rifampicin resistance. Furthermore, when Rifampicin resistance (RR) is seen, the patient is offered First Line (FL) and Second Line (SL) Line Probe Assay (LPA). RR detected in a new case with no risk factors for Drug-Resistant Tuberculosis (DR-TB) needs to be retested, only if M.tb detected was very low as that could be a false positive. If there is a discordance in Rifampicin resistance between NAAT and LPA, a second NAAT is performed at the Culture and Drug Susceptibility Test (C & DST) laboratory using the decontaminated deposit, and the microbiologist will provide the final decision. Additionally, direct LPA can be performed only on smear-positive specimens. In instances where the smear is negative, culture is set up, and if the culture is positive, an indirect LPA is performed on the isolate. 

Xpert Ultra is increasingly being used in the Private sector. Machine printouts of results from Xpert Ultra may be considered for guiding treatment; however, uncertainty in trace calls warrants clinical correlation / additional tests to be ordered by the treating physician.

 

2.4. Skin Test and Interferon-Gamma release assays (IGRAs) and Other Tests for TB

Tuberculin Skin Test (TST) is an intradermal injection of Purified Protein Derivative (PPD). (See Annexure 6 for TST technique) The current recommendation is to use 2TU PPD RT23 for all diagnostic purposes.  Mantoux’s test or PPD skin test is considered positive if the induration is 10 mm or more. In HIV co-infected cases, 5 mm may be taken as the cut-off. It is an immunological test that elicits delayed-type hypersensitivity. TST is used as an adjunct to other tests, and in the diagnosis of TB, it has the same connotation as a history of contact. A positive test indicates present or past infection with M.tb.  but cannot distinguish infection from disease. Currently, this test is not possible due to the non-availability of any form of the original lot of RT23 PPD. Most commercially available products are not from the standard mother lot and thus can cause problems in interpretation as the cut-offs derived for the standard product may not be applicable (Annexure 6). The utility of skin tests to assist the diagnosis of TB has decreased as the availability and sensitivity of microbiological tests has improved. 

Interferon-Gamma Release Assays (IGRAs), which provide an in vitro measure of M.tb hypersensitivity, offer the same information as TST and the tests currently approved by the WHO are TB Quantiferon Gold™ and TB Spot™ are available. Unlike Tuberculin Skin Test, they do not require a repeat visit for test reading and do not cross-react with BCG vaccination but need to be rapidly transferred to the lab and are expensive. A positive test marks the presence of TB infection in an individual but cannot confirm the presence of disease.

Diagnostics like serology (IgM, IgG, IgA antibodies against M. tb antigens), various in-house or non-validated commercial PCR tests and Bacillus Calmette–Guérin (BCG) tests are not recommended as TB diagnostic tools as they are often inaccurate. ESR is another test often used as a supportive investigation. Still, it is of no value in ruling in or ruling out the diagnosis of TB due to its non-specificity and the possibility to be affected by many variables other than the disease. A positive test result by either of the two available methods is not a reliable indicator that the person will progress to TB disease as the possibility of false-positive results cannot be ruled out. Conversely, a negative test result does not rule out TBI, given the case of a false-negative test result among at-risk groups, such as young children or among those recently infected.

C-Tb (Statens Serum Institut, Copenhagen, Denmark) is the next-generation skin test for the detection of TBI, which SSI Copenhagen has developed. It is an easy-to-use point-of-care test. It can deliver IGRA-like performance in a skin test format and uses a universal 5 mm cut off to differentiate the infected from the uninfected. The test is based on ESAT-6 and CFP-10 antigens (same as those used in IGRA) specific for M. tb and is unaffected by BCG vaccination. However, it is currently unavailable commercially and will be adopted in the programme once available and approved.

 

Extrapulmonary TB (EPTB) refers to any microbiologically confirmed or clinically diagnosed case of TB involving organs other than lungs, e.g. lymph nodes, pleura, bones, joints, intestine, genitourinary tract, meninges of the brain etc.

Presumptive Extrapulmonary TB refers to the presence of organ-specific symptoms and signs like swelling of lymph nodes, pain & swelling in joints, neck stiffness, disorientation etc. They may also have constitutional symptoms like significant weight loss, persistent fever for more than two weeks, night sweats. An effort should be made to establish microbiological confirmation in case of presumptive EPTB. Appropriate specimens from the likely sites of involvement must be obtained from every presumptive EPTB patient for NAAT/smear microscopy/ culture and DST for M.tb / histopathological examination etc., based on feasibility. Chest X-ray, USG, etc., are other investigations that can be used as supportive tools for diagnosing EPTB.

Sensitivity of NAAT for M.tb detection in pus, aspirate/biopsy specimen from lymph nodes, other tissue samples, and CSF is low to moderately high but poor in pericardial, ascitic and synovial fluid samples and still poorer in pleural fluid. A positive result by culture or NAAT provides useful confirmation. However, a negative culture or NAAT cannot rule out TB due to the inadequate sensitivity of these tests in extrapulmonary specimens. Therefore, if investigations like NAAT/smear microscopy/culture, etc., turn out to be negative or if an appropriate specimen is not available for these investigations, consultation with a specialist followed by other tests, e.g. histopathology, radiology, cytology etc. may be undertaken to reach a diagnosis. Often, the diagnosis in these situations is clinically based on suggestive history, presentation and other supportive investigations. Possible alternative diagnoses must be diligently ruled out in a patient who is clinically diagnosed to have TB.

 

4A. Rifampicin Sensitive Tuberculosis

4A.1. Basis of Pharmacotherapy

The choice of anti-TB drugs is based on several determinants such as bacillary and metabolic subpopulation, bacillary load, drug-resistant strains, pharmacokinetic profile, pathological factors, etc. There are different types of bacillary metabolic populations in every case of tuberculosis. Hence, drugs are selected in a combination to attack the entire (extracellular and intracellular, slow and rapidly growing) bacillary population for successful chemotherapy. Isoniazid (INH) and rifampicin (RMP) kill the fast-growing bacilli, pyrazinamide (Z) acts against intracellular organisms in an acidic medium, while RMP best kills extracellular slow-growing bacilli. Thus, every case of tuberculosis must be treated at least with these four drugs. Ethambutol (E) is recommended as the fourth drug in the intensive phase and as a third drug in the continuation phase due to high INH resistance (around 13% in new cases) in our country.

TB treatment is biphasic. The chances of naturally occurring mutants are higher if the bacillary load is more, and therefore, such cases need more drugs like in the initial stage of the disease. The Intensive Phase (IP) results in early and rapid killing of M. tb, prevent deterioration and death, reduces infectivity. Sputum conversion is achieved in 80-90%. In addition to PZA to RMP, INH minimises the duration of therapy to 6 months due to its sterilising effect. The addition of E is valuable if initial drug resistance to INH is high. The Continuation Phase (CP) eliminates most residual bacilli and thus reduces failures and relapses. As fewer bacilli are left after eight weeks of therapy, the continuation phase needs fewer drugs (usually RMP and INH). However, if there is a high prevalence of background resistance to INH, another medication may be necessary to prevent amplification of drug resistance during CP. In our country, the continuation phase has thus ethambutol added as the third drug for all new cases.

Standardised therapy with presumed drug sensitivity had been the way TB was treated until recent times, as testing for drug resistance was challenging and not pragmatic due to the long lead time. We currently understand that treating rifampicin-resistant strain with a standardised first-line regimen can lead to therapy failure and increase the risk of amplifying resistance to other drugs. Therefore, now first-line standardised regimen is only used after ruling out resistance to rifampicin upfront in all cases (U-DST). Molecular testing for rifampicin using a rapid test (e,g, Xpert Rif, Truenat, LPA) is now possible and available throughout the country. Molecular tests and liquid culture (MGIT™) are used to detect resistance to other drugs. The standard retreatment regimen (erstwhile category II) has been withdrawn due to the risk of poor outcomes and amplification of drug resistance. Furthermore, no routine extension of IP is done at the end of 2 months for a patient with slower or non-response; instead, investigations for DR-TB are carried out again.

As the dividing time of TB bacilli is about 21 hours, all the drugs are administered to achieve peak concentration at once to inundate the bacilli. Intermittent therapy has been replaced by daily treatment with continued treatment support.

Fixed Drug Combination tablets have replaced erstwhile combipacks and patient-wise boxes.  Furthermore, studies have also shown that most non-rifampicin resistance has poor outcomes due to INH mono/poly resistance. A new regimen for INH mono-poly resistance is advised (detailed in DR-TB section). Tests for INH resistance are carried out using first-line drug line probe assay (FL LPA) either directly on a clinical sample if it is smear-positive or on the isolate obtained through liquid culture. All Rifampicin-Sensitive TB (RS-TB) cases are given the standard therapy even if they have been treated in the past. Adjunctive surgical therapy may be needed in certain situations like spinal compression. As the anti-TB drug concentration achieved in a caseum and sequestrated tissue is poor, surgical removal should be done wherever feasible.

To summarise, now the patients are no more classified as New and Previously treated (see Box 2. for definitions) to allocate them standard four-drug (erstwhile category I) and five drug regimens (former category II). The primary aim is to segregate the patients upfront as rifampicin resistance detected (RR-TB) or rifampicin resistance not detected (RS-TB). All RS-TB cases are given the standard therapy even if they have been treated in the past. All patients undergo testing for other drugs, particularly for INH (mono or poly) and are treated with a different regimen if INH resistance is identified (discussed under DR-TB section).

 

Case Definitions 

 

Box 2. Case Definitions

 

4A. 2. Treatment Regimen

 

 

 

 

 

Table 3.  Treatment Regimen for Rifampicin-Sensitive TB

a. Molecular testing shall be done in all new cases in children with suspected TB at diagnosis and RSTB (Rifampicin resistance not detected) cases included in this regimen.

b. In the case of Neuro and spinal TB, the continuation phase is extended to 10 months.

c. All these categories of children shall be evaluated as DR-TB suspects and assessed as per the DR-TB Algorithm. DST based treatment shall be followed. If they are found to be Rifampin (and INH) sensitive, they shall be re-started on the regimen as for a new case. This group was earlier treated with CAT II regimen, which is now withdrawn from NTEP.

 

The drug dosages have been rationalised based on recent data on pharmacokinetics of ATT drugs and are as shown in the table below (Table 4):

 

 

 

 

 

Table 4.  Drug Dosages for Rifampicin-Sensitive TB Treatment

 

NTEP has introduced Fixed Drug Combinations (FDCs) incorporating multi-drug therapy for TB. FDCs are preferred due to safety, simplified treatment, and avoiding errors in missing one or more of the combination drugs, thus reducing the risk of emergence of drug-resistant strains. From a programmatic viewpoint, it has simplified drug supply management, shipping and distribution. FDC tablets of good quality and proven bioavailability of rifampicin are being used in combination in treating TB. 

 

There are two types of Paediatric FDCs available under NTEP-Formulation: Dispersible and Flavoured.

• For Intensive Phase (IP): 3 Drugs FDC Dispersible Tablets (DT) (H 50, R 75, Z150) (10:15:30) 
• For Continuation Phase (CP): 2 Drug FDC DT (H 50, R 75) (10:15) 

 

As Ethambutol is not available in the DT form, a non-DT 100 mg Ethambutol tablet is given for each Paediatric FDC during IP and CP.

There are two types of Adult FDCs available under NTEP, which are used in older children:

• For Intensive Phase: 4 FDC (H 75, R 150, Z 400, E 275)
• For Continuation Phase: 3FDC (H 75, R 150, E 275)

The therapy recommended as per body weight is detailed below (Table 5):

 

 

 

 

Table 5. Recommended Drug dosages and FDC Pill combination from 0-18 years of age

 

4A.3. Adjunct Therapy along with anti-Tuberculosis Drugs

I. Steroids in Tuberculosis

Definite indications for concomitant steroid therapy in TB include TB Meningitis, pericarditis, Addison’s disease, miliary TB with alveolo-capillary block and TB uveitis. The evidence in other forms of intracranial TB like tuberculomas is unclear. In addition, steroids may be used in endobronchial tuberculosis, bronchial compression, mediastinal compression syndrome, pleurisy with severe distress, laryngeal TB, TB Immune Reconstitution Inflammatory Syndrome (IRIS) and miliary disease with alveolo-capillary block.

Steroids decrease inflammation-related injury. They are shown to reduce the mortality in pericardial disease and improve outcomes in intracranial TB by reducing the development of hydrocephalus and vasculitis. Moreover, the interaction between the microbial factors and host immunological factors in the lung, lymph nodes, intracranial tuberculosis lesions may cause paradoxical worsening of symptoms due to the release of pro-inflammatory markers like IL 2 and Interferon-gamma. Most such cases recover with the continuation of therapy. However, few circumstances can have severe life-threatening manifestations and sequelae. In such cases, steroids may bring relief by suppressing inflammation. 

Steroids like prednisolone 1-2 mg/kg/day or dexamethasone 0.6 mg/kg/day or its equivalent are used for 2-4 weeks and then are tapered over the next four weeks. Any steroid in equipotent doses can be used. 

 

II. Adjunctive Pyridoxine Therapy 

Usually, no adjunctive therapy in the form of multivitamin or multi-mineral is advised as there is no evidence of these improving outcomes of TB patients. However, Isoniazid interferes competitively with pyridoxine (Pdx) metabolism by inhibiting the formation of the active form of the vitamin and can result in peripheral neuropathy.  Furthermore, earlier, the adjunctive vitamin B6 (Pyridoxine) was not recommended routinely for all children on TB treatment. Previously it was recommended only for high-risk groups like HIV, alcohol abuse, malnutrition, Diabetes Mellitus (DM), Renal failure, Liver failure, and Multi-Drug Resistant TB (M-DR TB) treatment and. Nonetheless, it is worth mentioning that earlier, every child in the continuation phase of the Intermittent Directly Observed Treatment (DOT) regimen was getting Pyridoxine on drug holidays. 

 

However, now there has been a rethink on the need for Vitamin B6 (Pyridoxine) supplementation due to: 

(a) increased dose of INH (10-15 mg/kg/d) has potential for an increase in dose-related adverse effects, 

(b) The high prevalence of malnutrition in children with TB makes them prone to peripheral neuropathy. Moreover, peripheral neuropathy in young children can go unrecognised and untreated with severe and prolonged morbidity.

Lastly, low cost, safety and lack of interference with INH action by the small prophylactic dose favour its use for likely benefit. Therefore, Pyridoxine (Vitamin B6) supplementation (10mg per day) is recommended to all patients receiving therapy with INH containing regimens.

 

4B. Monitoring and Follow-Up of Rifampicin-Sensitive Paediatric TB Cases

 

Children should be closely monitored for treatment progress and disease response. There are two components of follow up: 

1. Clinical follow up 
2. Laboratory follow up

 

Clinical follow up should be done every month during treatment. After completion of treatment, it may be done every six months for two years. Furthermore, an additional initial visit within two weeks of starting the therapy is desirable, where possible, to reassess that patient is on the correct dose and combination and is tolerating all drugs, 

 

I. Clinical Follow Up:

On each follow-up child should be assessed for the following:

a. Improvement in clinical symptoms, including cough, fever, appetite or other clinical signs. These will be assessed as no improvement, partial improvement or improved after asking parents or attendants. Most patients will show amelioration of symptoms by the end of four weeks of therapy.

b. Physical examination: This will include individualised relevant examination including respiratory rate, heart rate, temperature (if fever), blood pressure if indicated, chest examination for breath sound, crackles, evidence of pleural effusion, chest indrawing, recording of lymph node size, anaemia, abdomen for organomegaly or distension. Furthermore, examination of the relevant system, e.g. cardiovascular system in pericardial TB, the central nervous system in TBM or intracranial TB, etc., should be done. The physician will record their assessment as either no improvement, partial improvement or improvement.

Lastly, the treating physician should also record the child's weight (as precise to 0.1 Kg) by using an appropriate weighing scale (Bassinette type electronic weighing scale for infants and lever type scale for children who can stand) and check for weight gain in comparison to weight on the last visit. Causes of poor weight gain may be insufficient intake, vomiting, a side effect of medications, wrong diagnosis, comorbid conditions, concurrent infections such as diarrhoea, pneumonia or poor response to treatment. These causes will be assessed by asking history and performing the examination. If the assessment suggests no clinical deterioration, the family will be counselled for increasing food intake. Suppose a child is losing weight or is assessed to be unresponsive to treatment. In that case, they should be re-evaluated for TB, drug-resistant TB or alternative diagnosis by seeking expert advice. In a co-infected case, this may also signify Anti-Retroviral Treatment (ART) failure. With appropriate therapy, catch-up growth and the expected growth of a child as per age could remain unimpeded. This may necessitate an upward revision of drug dosage whenever a patient crosses his pre-treatment weight band.

c. Side effects of medications: Common side effects of ATT are given in table V. Most of these are minor and consist of vomiting, rashes, pain abdomen etc. Significant side effects of ATT include hepatotoxicity manifesting as nausea, vomiting, pain abdomen, poor appetite or clinically evident jaundice. The treating physician will also assess for rashes, visual acuity, colour vision for older children. The adverse effects of anti-TB drugs as well their management are outlined in subsequent chapters.

d. Treatment of Comorbid conditions like HIV, Severe Acute Malnutrition (SAM), DM etc., should be monitored during each visit. Decongestive measures and anti-convulsants are often prescribed in neurological TB and should be observed at follow-up. Refer for paediatric consultation in the case of pneumothorax or lungs collapse (manifested as respiratory difficulty on assessment). Similarly, in instances of a subacute intestinal obstruction, refer for gastroenterology and surgical opinion. 

e. Adherence to therapy should be revisited and ensured at each follow-up visit or unscheduled visit. Use Pill count, social support, family-based DOT and Treatment supervisor as needed.

 

 

 

 

Box 3. Interrupted TB Treatment

 

II. Monitoring by Laboratory Investigations will include sputum or gastric aspirate examination, imaging X-ray film of chest, Ultrasound abdomen, Echocardiography, CT scan of organ involved (Head, Chest, Abdomen) or MRI (spine). Lab investigation for side effects of medications comprises monitoring drug levels for antiepileptic drugs, Liver function test (LFT) if hepatotoxicity is considered or developed.

a. Microbiological:  The respiratory secretions, if available, are tested at the end of IP and completion of treatment (Bacterial negativity- sputum, GA etc. with smear and culture; repeat NAAT for any acquisition of Rif Resistance, if follow up smear is positive) 

Mycobacteria Growth Indicator Tube (MGIT) culture: should be performed if the child is not responding even after four weeks of therapy. However, as most of the children in their young years are unable to produce sputum or may have complete resolution of their cough and sputum. In such situations, response to treatment may need to be assessed clinically with help of radiological testing. Other relevant investigations may also be taken.

b. Liver function test: No routine or baseline LFT testing is required for patients on first-line drugs without evidence of any hepatopathy. These tests are done if any child shows symptoms or signs suggesting hepatic dysfunction.

c. Follow up Chest radiographs should be performed only at the end of therapy or earlier if assessed to be: clinically non-improvement, emerging complications or deterioration.

d. Other imaging, including Ultrasound of abdomen, echocardiography, CT/MRI scan of the affected organ system, is advised at the completion of treatment or when the patient is unresponsive to treatment or shows deterioration while on treatment. 

 

III. Clinical or Radiological non-response or Deterioration during follow up:

The causes for a clinical non-response could be: 

1. Incorrect diagnosis (particularly if a clinically diagnosed case of TB)
2. Lack of adherence to therapy 
3. Incorrect drugs or dosages
4. Inability to retain drugs- children often may vomit out medications due to the bad taste or upon forceful consumption of the medicine.
5. Secondary infection or a comorbidity
6. Drug resistance
7. Paradoxical upgrading reactions

Further pertinent investigations are decided based on clinical clues for any of the above conditions. Detailed analyses for drug resistance should be sent for MGIT DST or LPA, or CBNAAT.   Moreover, drug resistance should not be labelled without microbiological confirmation in most circumstances. Diagnosis of drug-resistant TB through bacteriological diagnosis is often untenable, with few notable exceptions where lack of access to appropriate specimen may not allow microbiological confirmation of drug resistance. History of contact with a proven case of M-DR or history of prolonged or irregular therapy in a source case within household or peer groups of the child is a good clue for suspecting DR-TB. Often such history is not available upfront but is provided later on follow-up by the family as they become more aware of the disease and may check around for such a case to whom the child may have been exposed.

Lastly, radiological deterioration alone without clinical symptoms should be reviewed with a skilled radiologist. The difference in respiration phase, rotation, and radiological factors can seriously affect the assessment of improvement (or lack of it) on follow-up images.

 

IV. Paradoxical Upgrading Reactions (PURs)

It refers to enlargement of existing lesions or unexpected appearance of new lesions during apparently adequate ATT. It usually occurs 3–12 weeks after the beginning of therapy, most frequently after treatment for 6- 7 weeks, & lasts for approximately two months. PURs are generally self-limiting and resolve without serious sequelae. It usually regresses without a change of initial drug regimen. It may occur post-treatment (as late as two years) in cases of lymph node TB as the retained caseum may track up and result in sinus formation.

Active TB can result in depression of immunity. Nevertheless, after successful ATT, the focal immune response improves. Accumulation of inflammatory exudates at previously invisible microscopic tuberculous foci elsewhere may appear as new lesions. Reversible roentgenographic progression in the initial treatment of TB may be more common than previously expected if there is frequent monitoring by chest radiograph. It is for this very reason, routine monitoring by radiographs is not recommended.

Types of reported Paradoxical Upgrading Reactions (PRUs)

• Increase in size of mediastinal lymph nodes or areas of pulmonary infiltration in paediatric patients with primary TB
• Appearance of new lung infiltrates in patients with extrapulmonary TB
• Development of TB pleural effusion
• Increase in size of effusion/appearance of effusion on the contra lateral side
• Appearance of new lymph nodes/ enlargement of original nodes
• Increase in size or number of tuberculoma/ infarctions / hydrocephalus on treatment of intracranial TB

 

 

 

 

Box 4. Types of reported Paradoxical Upgrading Reactions (PRUs)

 

The absence of any systemic symptoms is a helpful indicator of PUR. Moreover, a lack of systemic symptoms is usually seen in paradoxical reactions (non-HIV settings). It might be difficult to distinguish a paradoxical response from an actual drug resistance TB- and thus, PUR is never diagnosed without excluding DR-TB. 

 

V. Long-term follow up: After completion of treatment, the patients should be followed up every six months for two years to assess for early detection of any relapse of illness. Monitoring on each visit will include the same as described above. 

 

DR-TB refers to the presence of drug resistance to any of the first-line or second-line drugs. The definitions below explain the terminology used for various types of drug resistance. Resistance to some key drugs has more severe consequences than others, e.g. resistance to INH or Rifampicin clearly compromises the initial four-drug therapy. Likewise, additional resistance to Group A second line drugs like Fluoroquinolones (FQ) or newer drugs like Bedaquiline or Linezolid in a patient with MDR-TB seriously impacts therapy with second-line drugs.

Prevalence of MDR-TB, i.e. M. tuberculosis resistant to isoniazid and Rifampicin with or without resistance to other drugs, is estimated to be about 2.8% (2.3–3.5) among new cases and 14% (12–17) among the previously treated patients[1].

Minimal data is available regarding MDR-TB in children. In children, it primarily results from the transmission of drug-resistant bugs from the source case (usually adolescents and adults). Less commonly, it does also result from previous inadequate TB treatment. The prevalence of MDR-TB in children mirrors MDR-TB in adults. Thus, it is common in settings where the MDR-TB pool exists in adults and is associated with higher morbidity and mortality than the drug-sensitive disease.  

 

Based on the pattern of drug resistance, the cases may be further classified for treatment purposes as:

a. Mono-resistant TB (MR-TB). A TB patient whose biological specimen is resistant to one first-line anti-TB drug only.

b. Isoniazid-resistant TB (Hr-TB). A TB patient whose biological specimen is resistant to isoniazid and susceptibility to Rifampicin has been confirmed.

c. Poly-drug resistant TB (PDR-TB). A TB patient whose biological specimen is resistant to more than one first-line anti-TB drug, other than both H and R.

d. Rifampicin-resistant TB (RR-TB). A TB patient whose biological specimen is resistant to R detected via phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to R in the form of mono-resistance, poly-resistance, MDR or XDR.

e. Multidrug-resistant TB (MDR-TB). A TB patient whose biological specimen is resistant to both H and R with or without resistance to other first-line anti-TB drugs. MDR-TB patients may have additional resistance to any/all FQ or any other anti-TB drug.

f. Pre-extensively drug-resistant TB (Pre-XDR-TB). TB is caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone.

g. Extensively drug-resistant TB (XDR-TB). TB is caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone (levofloxacin or moxifloxacin) and at least one additional Group A drug (presently to either bedaquiline or linezolid [or both]).

h. Extensive (or advanced) TB disease refers to the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. 

i. Severe extrapulmonary TB refers to the presence of miliary TB or TB meningitis extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are considered as severe (adapted from Wiseman et al., 2012 (7)).

 

A. Approach to Diagnosis of DR-TB in Children:

As there are no clinical disease patterns that can identify the presence of drug resistance in a given case, epidemiological markers, when present, can suggest possible DRTB. However, these markers are not always present. Moreover, first-line drug regimens fail and have an added risk of amplifying resistance to other companion drugs if resistance to Rifampicin and INH is present. Therefore, there has been a shift to identifying the presence of these key resistance in all TB patients at diagnosis (universal DST), replacing the earlier approach of targeted testing for DRTB among the patients more likely to harbour drug resistance strain (presumptive DR-TB cases). Universal DST (U-DST) refers to universal access to rapid DST for at least Rifampicin (and where possible INH). It also includes DST for fluoroquinolones among all TB patients with Rifampicin resistance (preferably before initiation of treatment or as soon as possible).

 

Epidemiological Markers for DR-TB:

Important epidemiological markers for DR-TB include: 

• finding a history of contact with suspect MDR
• details of previous poor treatment (inadequate drugs, dosage and duration) and lack of adherence
• in a patient not responding to therapy, or those with recurrence of disease after previous treatment, as such cases could be harbouring a drug-resistant strain.  
• it must be added that the causes of non-response to anti-TB therapy include incorrect diagnosis of TB, poor adherence, paradoxical upgrading reactions, and other untreated coexisting or inter-current co-infections.  
• TB among Children living with HIV (CLHIV) or those in contact with someone dying of TB is also found to have a higher likelihood of DRTB. 

 

Confirmation of Drug Resistance:

Confirmation of drug resistance is always by microbiological methods (genotypic and phenotypic). Getting appropriate body fluid samples for pulmonary or EPTB patients is crucial for mandatory microbiological confirmation and drug susceptibility testing. For this, sputum (or other alternative respiratory specimens, e.g. gastric aspirate or lavage for swallowed sputum, induced sputum, bronchoscopic lavage) or other relevant specimens like lymph node aspirates, CSF analysis, pleural or pericardial or peritoneal fluid, tissue biopsies must be collected in all children with presumed DR-TB for NAAT (e.g. Truenat/ Xpert M.TB  RIF), LPA and culture and drug sensitivity testing. This may imply a referral to a higher centre to facilitate detailed and sometimes invasive testing.

In a presumptive DR-TB patient, if all efforts for microbiological confirmation have failed or confirmation is not possible due to inaccessible specimen, but the clinical probability of it being DRTB is high (failure of adequate first-line therapy and/or close contact of a proven MDR-TB case), and there is no alternative diagnosis or explanation for non-response the patient may be treated as a clinically diagnosed DR-TB (Probable MDR-TB).   In such situations, drug regimen can be decided based on the drug sensitivity pattern of the DRTB contact (likely source case), where available. Moreover, the patients considered to have 'probable' MDR-TB should be presented to and discussed with the DR-TBC Committee for confirming the decision to treat in consultation with a paediatrician. 

Furthermore, in children with a severe disease like central nervous system TB or other life-threatening manifestations who have substantial risk factors for DR-TB, treatment as probable MDR-TB can be initiated, pending confirmation, in consultation with the paediatrician in the Nodal DR-TB Centre (NDR-TBC) committee, given their high risk of mortality. Further treatment in such situations can be decided based on their test results as and when available.

 

 

 

 

 

Box 5. Probable MDR-TB Among Children

 

 

 

 

 

Box 6. Confirmed Drug-resistant TB cases

 

 

 

Additional Consideration:

Practitioners need to know which medicines have frequently been used in a given geographical setting or patient group. Moreover, practitioners should strive to test for drug resistance and limit empiric treatment to a minimum despite some uncertainties about DST. The patient's clinical response to treatment should constantly be carefully monitored. If there is poor treatment response, undiagnosed resistance should be considered, as should alternative explanations for failure to respond to treatment (e.g. poor or erratic adherence to treatment, immune reconstitution inflammatory syndrome (IRIS) or the presence of comorbidities.

 

B. Methods for Drug Susceptibility/Drug Resistance Testing:

I. Drug Resistance Tests Using Molecular Methods: 

This can be performed on sputum specimens (direct) or culture isolates (indirect) for diagnostic purposes. Presently the following technologies are available for diagnosis of DR-TB through rapid molecular diagnostic testing:

a. Nucleic Acid Amplification Test (NAAT) (viz. Xpert MTB RifTM test using the Gene-Xpert platform /TrueNatTM): These NTEP approved, cartridge / chip-based NAATs can be performed on smear-positive, smear-negative and extrapulmonary specimens as they can detect DNA even with few copies. The tests detect M. tb as well as resistance to Rifampicin in the MTB. The test time is about two hours.

b. Line Probe Assay (LPA) refers to molecular test(s) used for (a) detection of MTB complex and rapid diagnosis of R and H resistance (FL-LPA), (b) resistance to class FQ and class SLID (SL-LPA). LPA needs many DNA copies (over 10,000 per ml) for detection and thus can be used directly only on smear-positive specimens. The processing time is 72 hours each for both first- and second-line LPA. In addition, LPA can be used for genotypic drug sensitivity on an isolate from culture (like MGIT) from any specimen, including smear-negative samples. This mixed-method approach could decrease turnover as the phenotypic sensitivity testing would take weeks compared to a few days with LPA.

c. Xpert M.TB /XDR

This newer version of Cartridge Based NAAT can detect mutations associated with resistance towards H, FQ, SLI and Eto in a single test, using a semi-quantitative nested PCR followed by high-resolution melt technology. It requires GeneXpert platforms equipped with 10-colour modules. Test processing time is about 90 minutes.  

• When endorsed, the test is suited to follow molecular tests that detect M. TB/Rifampicin resistance. 
• It can potentially improve access to rapid drug susceptibility testing, especially for ruling out fluoroquinolone resistance, which is required before starting the shorter oral Bedaquiline-containing MDR/RR-TB regimen.

 

These methods are PCR-based and cannot be used for determining response to treatment, unlike a smear.

 

II. Growth-Based Phenotypic Drug Susceptibility Testing:

M. tb Culture, though a highly sensitive and specific method for TB diagnosis, requires 2-8 weeks to yield results and hence does not allow rapid confirmation, unlike molecular tests. Culture, however, needs to be used for long-term follow-up of patients on DR-TB treatment and help detect early recurrence in both drug-sensitive and drug-resistant TB. The growth-based phenotypic culture methods include automated Liquid culture systems, e.g., BACTEC MGIT 960, BacTAlert or Versatrek etc., and solid (Löwenstein Jensen) media. 

 

Mycobacteria growth indicator tube (MGIT) is currently the preferred method for DST under NTEP, and both first and second-line anti-TB drugs sensitivity can be tested by this method. Following drugs can be tested for susceptibility by liquid culture:

• First-line drugs: R, H, E, Z
• Second-line drugs: S, Lfx, Mfx, Km, Cm, Am, Lzd, Cfz*, Bdq*, Dlm etc.

 

Phenotypic testing also determines the critical inhibitory concentrations of various drugs to guide therapy. It could save time by running a molecular genotypic test (LPA) on a culture isolate if the initial specimen was unsuitable due to smear negativity. 

 

Important notes to microbiological testing and result interpretation:

• Ideally, two specimens should be collected from every patient and sent to the NAAT facility, who shall run the NAAT and transmit or test the other aliquot for M. tb culture.
• Samples must be transported immediately after collection to the linked laboratory for appropriate testing. Standard Operating procedure for triple-layer packaging must be strictly adhered to, and the sample must be transported in a cold chain. Samples must not be batched. 
• EPTB samples should not be collected in Formalin for bacteriological tests (genotypic as well as phenotypic).
• Airborne Infection Control (AIC) measures must be followed at all times. Biomedical Waste Management must be ensured.
• If R resistance is detected on NAAT, the patient is offered First Line (FL) and Second Line (SL) LPA followed by LC DST as indicated in the algorithm.
• If R resistance is detected with a very low level of M. tb in a patient with low clinical suspicion, it should be confirmed by a repeat specimen for NAAT.
• Suppose R resistance is not detected on NAAT. In that case, the patient is offered FL LPA for detecting resistance to H. All H resistant patients are subsequently offered SLLPA followed by LC DST as indicated in the algorithm.
• Treatment is initiated based on LPA results and modified based on the LC DST results, available later.
• Phenotypic DST for ethambutol, ethionamide may be inaccurate and not reproducible. No agreed DST methods had been established for some other second-line drugs [e.g. cycloserine/terizidone, imipenem- cilastatin/meropenem and P-Aminosalicylic Acid (PAS)].

 

 

C. Integrated Drug Resistant TB Algorithms

 

 

 

 

 

 

Figure 5. Integrated diagnostic and treatment algorithm for drug resistant tuberculosis

 

 

 

 

 

Figure 6. Algorithm approach to diagnosis of DR-TB in children

 

 

 

 

  Figure 7. Specimen Flow and Operational Processes

 

 

5.1.  Treatment of Drug Resistant TB in Children

Compared to drug-susceptible TB (DS-TB) treatment, DR-TB regimens require a longer course, higher pill burden, and higher toxicity profile, resulting in lower adherence and poorer treatment outcomes, including deaths. The principles of designing a WHO-recommended regimen section also applies to the paediatric population. 

• Include at least 4-5 effective medicines from Group A and B to which the Mycobacterium tuberculosis strain is known or likely to be susceptible.
• Do not add a single drug to a failing regimen to avoid amplification of resistance.
• Strict monitoring of treatment by clinical examination, radiology and culture response to be undertaken by paediatrician/ expert available/ linked to DR-TBC.

Children aged five to less than 18 years of age and weighing at least 15 kg are eligible for both Shorter or Longer oral MDR/RR-TB regimens. Furthermore, the pre-treatment evaluation carried out at the treatment initiation can be considered valid for one month from the test result. The patient can be re-initiated on a subsequent regimen based on this. In addition, long term follow-up will be done with six-monthly cultures among symptomatic patients till two years after completion of any DR-TB regimen, i.e. months 6, 12, 18 and 24 post-treatment. Lastly, Active Drug Safety Management and Monitoring (aDSM) treatment initiation form need to be completed for all DR-TB patients at the time of initiation of each new episode of treatment.

 

5.1.1. Grouping of Drugs

The anti-TB drugs recommended for MDR/RR-TB patients are grouped based on efficacy, the experience of use, drug class and aligned with revised classification as per WHO Consolidated Guidelines for TB Module 4: Treatment of Drug-Resistant TB (2020). 

 

 

 

 

 

 

Table 6. Grouping of anti-TB drugs and steps for designing a longer MDR-TB regimen

 

 

 

5.1.2. Standard DR-TB Regimens Available Under NTEP

The NTEP Treatment Expert group (Paediatric), India, has agreed to the following regimens for our country, keeping in view the WHO advice. 

 

 

 

 

 

 

 

Figure 8. Treatment Algorithm for DR-TB in Children

• * As per the exclusion criteria (mentioned in details in this chapter and Annexure 6) for the shorter MDR-TB regimen, while considering the option of longer oral regimen, shortening the total treatment duration may be considered depending upon the response (12 to 18 months) but not less than 12 months in any case.
• ** Can be given in all children with extensive disease.  However, for children under five years of age where neither Bdq nor Dlm is approved yet, the longer oral M/XDR-TB regimen is suitably modified with replacement of Group C drugs for longer oral M/XDR-TB regimen in the sequence of -  amikacin, pyrazinamide, ethionamide, PAS, ethambutol, penems.
• ***In conditions like: extensive pulmonary disease; uncontrolled underlying morbidity; extrapulmonary TB (other than isolated pleural effusion or peripheral lymphadenopathy) or any change in the standardized regimen necessitated by drug resistance or intolerability to any drug of the regimen, the therapy is increased to 9 months. For cases with spinal and neuro TB, the total duration is 12 months.
• #dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment

 

5.1.3. Special Considerations for M/XDR-TB in Children

• Always treat in consultation with an expert, preferably paediatrician available/ linked.
• Bedaquiline(Bdq) will be given to children more than five years of age weighing 15kg or more.
• Delaminid(Dlm) will be given to children six years onwards. Although WHO has approved the use of Dlm in the age group 3-5 years, the regulatory approval in India is awaited.
• Delaminid(Dlm) will be considered only as a replacement in a longer oral M/XDR-TB regimen.
• To modify the longer oral M/XDR-TB regimen, the N/DDR-TBC physician must review the resistance pattern, tolerability history, contraindications, and availability of first and second-line drugs to identify the number of drugs from Group A and Group B that need to be replaced.
• In special situations, an extension of Bdq beyond six months and concomitant use of Bdq and Dlm can be done.
• The regimen should preferably be entirely oral. However, injectables may have to be used for efficacy and side-effect profile in certain circumstances.
• The avoidance of an injectable-containing regimen is particularly desirable in children. Given the profound impact that hearing loss can have on the acquisition of language and the ability to learn at school, the use of injectable agents in children should be exceptional under strict monitoring to ensure early detection of ototoxicity.
• For paediatric patients, the drug dosage should be adjusted immediately once the patient's weight crosses the range of weight-band and counselling regarding the change in weight band and the change in the number of pills that need to be consumed.
• Child-friendly (dispersible and palatable) formulations should be used whenever available.
• Bedaquiline tablets suspended in water have been shown to have the same bioavailability as tablets swallowed whole and can therefore be used to treat drug-resistant TB in children until a child-friendly formulation becomes available.
• Clavulanic acid should be included in MDR/RR-TB regimens only as a companion agent to the carbapenems (Imp-Cln and Mpm). When used in this way, it should be given with every dose of carbapenem and should not be counted as an additional effective TB agent.
• Seizures may be more common in children with meningitis treated with imipenem, and meropenem is preferred for cases of TB meningitis and in children.
• The monitoring of DR-TB treatment in children is the same as in adults. However, for probable MDR-TB patients, the paediatrician available at or linked to the N/DDR-TBC must regularly evaluate the child's progress on treatment and initiate any other investigations as deemed necessary.

 

5.2. (H) mono/poly DR-TB regimen in Children

(6) Lfx R E Z

• Duration is of 6 or 9 months with no separate IP/CP.
• The patient is initiated on (6) Lfx R E Z when found to be resistant to INH (but not Rifampicin) based on the First-line Line Probe Assay (FL-LPA) report. The regimen could be modified subsequently based on SL-LPA results.
• If H mono/poly DR-TB is detected, the FL- LPA deposit is subjected to SL-LPA by the lab and LC-DST to Mfx, Z, Lzd, Cfz*(*Whenever DST is available).
• If there are signs of non-response, the patient must be subjected to NAAT again to rule out amplification of Rifampicin resistance and further LPA and DST.
• In conditions like - extensive disease, uncontrolled comorbidity, extrapulmonary TB or any change in drug of standardized regimen due to additional drug resistance or intolerability to any drug, the regimen is increased to 9 months.
• In exceptional situations of unavailability of loose drug R or E or Z, the use of 4 FDC (HREZ) with Lfx loose tablets may be considered as an option rather than not starting the treatment.
• The dosage of drugs would vary as per the weight of the patients.
• All drugs in the regimen are to be given daily under observation.

 

 

5.2.1. Replacement Sequence

Replacement is done in case of additional resistance, intolerance, unavailability or contraindication of the component drugs of the regimen.

 

 

 

 

 

 

*whenever DST is available

Table 8. Standard Replacement sequence of drugs to modify H mono/poly DR-TB regimen

 

 

5.2.2 Follow up Monitoring

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 9. Follow up evaluation schedule of H mono/poly DR-TB patients

• 1Lzd containing regimen to rule out bone marrow suppression
• 2 HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice
• 3 In case of baseline ECG abnormality or QTcF ≥450ms for regimen containing Mfx(h) or Cfz, ECG must be done on daily basis for initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
• DST whenever available
• Urine Pregnancy Test (UPT)

 

5.3. Shorter oral Bedaquiline-containing MDR/RR-TB Regimen

(4-6) Lfx, Cfz, Z, E, Hh, Eto (6) Bdq | (5) Lfx, Cfz, Z, E

Eligibility Criteria

Children, aged five years to less than 18 years of age and weighing at least 15 kg, in consultation with a paediatrician

A. Inclusion Criteria

I. DST based inclusion criteria

• Rifampicin Resistance detected/inferred
• MDR/RR-TB with H resistance detected/inferred based on InhA mutation only or based on KatG mutation only (not both)
• MDR/RR-TB with FQ resistance not detected

II. Non-DST based inclusion criteria

• No history of exposure to previous treatment with second-line medicines in the regimen (Bdq, Lfx, Eto or Cfz) for more than one month (unless susceptibility to these medicines is confirmed);
• No extensive TB disease
• No severe extrapulmonary TB
•  

B. Exclusion criteria

I. DST based Exclusion Criteria

• MDR/RR-TB patients with H resistance detected with both KatG and InhA mutation or MDR/RR-TB patients with FQ resistance detected

II. Other Exclusion Criteria

• those with a history of exposure for > 1 month to Bdq, Lfx, Eto or Cfz. (If the result for FL-LPA, SL-LPA and DST to Z, BDQ & Cfz is not available)
• Intolerance or risk of toxicity from a drug in shorter oral Bedaquiline-containing MDR/RR-TB regimen.
• Extensive TB disease: bilateral cavitary disease or extensive parenchymal damage on chest radiography. 
• In children aged under 15 years, presence of cavities or bilateral disease on chest radiography.
• Severe EP-TB disease: the presence of miliary TB or TB meningitis or central nervous system (CNS) TB.
• In children aged under 15 years, extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression)
• Children below five years 

 

C. Duration of Regimen

• The regimen consists of an initial phase of 4 months that may be extended up to 6 months and a continuation phase of 5 months, giving a total duration of 9–11 months. Bdq is used for a duration of 6 months.
• From start to the end of 4 months: Bdq, Lfx, Cfz, Z, E, Hh, Eto   
• From the start of 5 months to end of 6 months – (If IP not extended) – Bdq, Lfx, 
• From the start of 6 months to the end of 9 months – Lfx, Cfz, Z, E
• If the IP is extended up to 6 months, then all three drugs Bdq, Hh and Eto, are stopped together.

 

D. Treatment Extension

 If sputum smear microscopy does not become negative by the fourth month of the treatment, subject the patient to FL-LPA, SL-LPA and culture & DST, and the IP should be extended. IP can be extended to the 5th or 6th month based on smear results at the end of the 4th and 5th months of treatment. T (total duration of IP is not more than six months). If any additional resistance to Z/Cfz on C&DST of the baseline sample is detected or to FQ/ inhA mutation of the 4th-month sample is detected, the patient needs to be reassessed at N/DDR-TBC for stopping shorter oral Bedaquiline-containing MDR/RR-TB regimen and initiation of longer oral M/XDR-TB regimen, immediately on receiving the report. The duration of CP is fixed for five months.

Details on erstwhile Shorter Injectable Containing Regimen could be found in Annexure 6.

 

E. Pre-Treatment Evaluation

 

 

 

 

 

 

Table 10.  Pre-Treatment Evaluation for Shorter oral Bedaquiline-containing MDR/RR-TB Regimen

 

 

F. Follow-up evaluation schedule during treatment

 

 

 

 

 

 

 

 

 

 

Table 11.  Follow-up evaluation schedule for Shorter oral Bedaquiline-containing MDR/RR-TB Regimen

 

• If smear/ culture remains positive at the end of the third month or by the end of IP respectively or extended IP, a fresh specimen/culture isolate of that time will be subjected to FL-LPA and SL-LPA to check for amplification of resistance to FQ and H (both inhA and katG mutation).
• If no additional resistance is detected, the IP is extended monthly up to a maximum of 6 months.
• If bacteriological reversion is ascertained or if FL-LPA or SL-LPA detects any resistance or if found to be smear/culture positive at the end of six months or later, the patient will be declared as ‘treatment failed’ and re-evaluated for the longer oral M/XDR- TB regimen.
• Once treated with the shorter oral Bedaquiline-containing MDR/RR-TB regimen for more than one month, a patient will never be reinitiated on it again.

 

 5.4. Longer oral M/XDR-TB Regimen

(18-20) Lfx, Lzd[2], Cfz, Cs (6)Bdq (6 m or longer)

 

A. Duration of Regimen                            

18-20 months with no separate IP or CP

 

B.  Eligibility Criteria

• MDR/RR-TB patients who are excluded from shorter oral Bedaquiline-containing MDR/RR-TB regimen.
• Additional resistance to any second-line drugs, especially Lfx, Mfx, Bdq* Lzd*, Cfz*, Dlm* and Z (*whenever available) or intolerance or non-availability of any drug in use.
• Return after Lost-To-Follow Up (LTFU) or failed to shorter oral Bedaquiline-containing MDR/RR-TB regimen or any longer regimen.
• However, as mentioned previously, for children under five years of age where neither Bdq nor Dlm is approved yet, the longer oral M/XDR-TB regimen is suitably modified as per the replacement sequence.

C. Pre-treatment evaluation (PTE)

The list of investigations enumerated for shorter oral Bedaquiline-containing MDR/RR-TB regimen will remain applicable to longer oral M/XDR-TB regimen. Additional investigations specific to group C drugs that may be required in situations where the longer oral M/XDR-TB regimen may need to be modified are as under:

• Blood Urea & Serum Creatinine – if Am need to be added
• Ophthalmologist opinion (for Linezolid)
• Surgical evaluation for consideration after culture conversion is achieved

Once a patient is placed on the longer oral M/XDR-TB regimen for at least four weeks, such a patient can no longer be switched to the shorter oral Bedaquiline-containing MDR/RR-TB regimen because this 4-weeks treatment would represent exposure to second-line medicines.

D. Treatment Extension

• Total duration of longer oral M/XDR-TB regimen is 18-20 months.
• After month 6 of treatment, the patient is reviewed based on the month five culture result. If the month five culture result is not available at the end of month 6, the decision to taper the dose of Lzd from 15mg/kg body weight to 10 mg/kg body weight based on the month four culture result.
• If the month 5 or 4 culture result (whichever applicable) remains positive, the dose of Lzd (15 mg/kg) and the regimen is extended by one month to month seven and for a maximum till month eight based on monthly culture results of month 6 and 7 respectively and clinical/radiographic response.
• If the month eight culture is also positive, subject the culture isolate to FL-LPA and SL-LPA and Culture & DST.
• If any additional resistance to Group A, B or C drugs in use is detected, the patient needs to be reassessed at N/DDR-TBC to modify the longer oral M/XDR-TB regimen.
• The duration of Bedaquiline is limited to 6 months.
• Extension of Bedaquiline beyond six months is considered in patients in whom an effective regimen cannot be designed, i.e. if only 2 of 5 drugs are available from Groups A & B and an adequate number of Group C drugs are not available due to high background resistance, non-availability or unreliability of DST.
• The maximum duration of treatment is not more than 20 months.
• A treatment duration of 15–17 months after culture conversion is suggested for most patients; the time may be modified according to the patient’s response to treatment.
• In XDR-TB patients, the duration of all oral longer regimen is of 20 months.

 

E. Replacement Sequence:

As per the 2021 Guidelines for PMDT in India following principles apply to the replacement of any of the component(s) in the longer oral M/XDR-TB regimen:

• The drugs replacement is based on efficacy, no demonstrable resistance, prior use, side-effects profile and background resistance to the replacement drug in the country as per the National Drug Resistance Survey (NDRS) report.
• The regimen should preferably be entirely oral.
• Sometimes injectables may be used based on efficacy and side-effect.
• At least 4-5 drugs are to be used in the initial 6 to 8 months, and at least 3-4 drugs in the last 12 months.
• In situations where no drug replacement is required in the first 6 or 8 months of treatment in MDR-TB or XDR-TB patients, continue with at least three drugs after this depending upon resistance, tolerability, availability, contraindication etc. of any one of Group A or B drugs.
• Replacement sequence of Group C drugs for longer oral M/XDR-TB regimen was recommended in the order of - Delamanid, Amikacin, Pyrazinamide, Ethionamide, PAS, Ethambutol, Penems.
• Combined use of Bdq and Dlm in the regimen is recommended for those M/XDR-TB patients in whom an appropriate regimen cannot be designed using all five drugs from Group A and B.
• Dlm and Am will not be started in the final 12 months of treatment.
• Though Imp-Cln is 4th in the sequence of drugs of group C in WHO guidelines, it will only be used as the last resort for designing the regimens, operational issues of a Peripherally Inserted Central Catheter (PICC) placement for the entire duration of its use, need for admission.
• Table for replacement sequence of using drugs to modify the longer oral M/XDR-TB regimen is placed as annexure (Annexure 5)

 

F. Follow-up Monitoring

 

 

 

 

 

 

 

 

 

 

 

Table 12.  Follow up evaluation schedule of longer oral M/XDR-TB regimen during treatment

• ^ If Lzd is part of the regimen to rule out bone marrow suppression.
• # HBsAG and other viral markers (Hepatitis A, C & E) to be done in case of Jaundice.
• $ In case of baseline ECG abnormality or QTcF ≥450ms with longer oral M/XDR-TB regimen that contains Bdq, Mfx, Cfz or Dlm, ECG must be done on daily basis for initial 3 days or as suggested by cardiologist. Repeat ECG with long II lead after an hour to reconfirm abnormal ECG.
• * DST whenever available.

 

G. Management of Treatment Interruptions and Lost to Follow-up

 

Patients Who Miss Doses:

All missed doses during IP must be completed before switching the patient to CP. Similarly, all missed doses during CP must be administered prior to ending treatment.

Patients who interrupt treatment for less than two months: The treatment will be continued, and the duration of treatment will be extended to complete the regimen. The follow-up cultures will be done as per the schedule. An additional culture may be considered if the patient returns between one to two months of treatment and has clinically deteriorated. 

• If the culture is positive - repeat FL/SL LPA, and LC DST need to be done as per diagnostic algorithm. If additional resistance is detected to any component drugs, the patient will be switched to the longer oral M/XDR-TB regimen with a fresh PTE. 
• If the interruption is in IP, the outcome will be accounted for this patient for the longer oral M/XDR-TB regimen only. If the interruption is in CP, the outcome for a shorter oral Bedaquiline-containing MDR/RR-TB regimen will be declared ‘treatment failed’.

Patients who are “lost to follow-up” (interrupt treatment continuously for two months or more) - give an outcome of “lost to follow-up”. 

• Subject to repeat NAAT & FL/SL-LPA and LC-DST as per the diagnostic algorithm to restart with appropriate treatment. 
• Suppose there are signs of impending treatment failure for any MDR/RR-TB patient with or without additional resistance to second-line drugs. In that case, the patient should be switched to the longer oral M/XDR-TB regimen and evaluated further to modify appropriately based on DST results.
• If a patient has received the shorter oral Bedaquiline- containing MDR/RR-TB regimen for more than one month and returns for treatment after continuous interruption of two months or more, the patient is not restarted on a shorter oral Bedaquiline-containing MDR/RR-TB regimen.

 

H. Paediatric Drug Dosages

 

 

 

 

 

 

Table 13.  Paediatric Drug Dosages

 

 

[1] Central TB Division, MoHFW G of I. Report of the First National Anti-Tuberculosis Drug Resistance Survey India 2014-2016. Available at: https://tbcindia.gov.in/showfile.php?lid=3315

[2] dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment

A second-line TB drug: This is an agent reserved for the treatment of drug-resistant TB. First-line TB drugs used to treat drug-susceptible TB – ethambutol, isoniazid and pyrazinamide – may also be used in MDR-TB regimens (streptomycin is now considered a second-line TB drug and used only as a substitute for amikacin when amikacin is not available or there is confirmed resistance to it).

 

Active case finding (ACF): It is defined programmatically as systematic screening for TB disease through outreach activities outside health facility settings. 

 

At-risk Group: Is any group of people in whom the prevalence or incidence of TB is significantly higher than in the general population. 

 

Bacteriologically confirmed TB: TB diagnosed in a biological specimen by smear microscopy, culture or a World Health Organization-endorsed (WHO) rapid molecular test and adopted by NTEP such as Xpert MTB /RIF®/Truenat®. 

 

Child: For the programmatic purpose in India, a child is a person up to and including 18 years of age. (This includes adolescents aged 10–18 years). 

 

Contact: Is any individual who was exposed to a person with active TB disease.

 

Contact investigation: It is a systematic process for identifying previously undiagnosed people with TB disease and TB infection among the contacts of an index TB patient or other comparable settings where transmission occurs. Contact investigation consists of identification, clinical evaluation and testing and provision of appropriate anti-TB treatment (for people with confirmed TB) or TB preventive treatment (for those without TB disease)]. 

 

Close contact: This is a person who is not in the household but shares an enclosed space, such as at a social gathering, workplace or facility, for extended periods during the day with the index TB patient during the three months before the commencement of the current TB treatment episode. This Group will be included for all interventions as applicable for household contacts in these guidelines. 

 

Drug susceptibility testing: DST refers to in-vitro testing using either of the phenotypic methods to determine susceptibility. 

 

Drug resistance testing: DRT refers to in-vitro testing using genotypic methods (molecular techniques) to determine resistance. 

 

Extensively drug-resistant TB (XDR-TB): TB caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone (levofloxacin or moxifloxacin) and at least one additional Group A drug (presently to either Bedaquiline or linezolid [or both]).

 

Extent or severity of the disease: In patients older than 18 years, this is usually defined by the presence of cavities or bilateral disease on chest radiography or smear positivity. In children under 18 years, severe disease is usually defined by the presence of cavities or bilateral disease on chest radiography or extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression). In children, the occurrence of advanced malnutrition (defined by syndrome or by metrics) or advanced immunosuppression or positive tuberculosis (TB) bacteriology (smear, NAAT, culture) may also be considered when determining disease severity. 

 

High TB transmission setting: This is a setting with a high frequency of individuals with undetected or undiagnosed TB disease, or where infectious TB patients are present, and there is an increased risk of TB transmission. (TB patients are most infectious when they are untreated or inadequately treated. The transmission will be increased by aerosol-generating procedures and by the presence of susceptible individuals. These settings with healthcare workers, prisoners, miners, slum dwellers, tribal, migrant labourers etc., could be mapped out as part of the vulnerability mapping exercise done for and prioritized by states for specific TPT interventions guided by differential TB epidemiology in the respective state). 

 

Index patient of TB: This is the initially identified person of any age with new or recurrent TB in a specific household or other comparable settings in which others may have been exposed. (An index TB patient is a person on whom a contact investigation is centred but is not necessarily the source). 

 

Infant is a child under one year (12 months) of age.

 

Isoniazid-resistant TB (Hr-TB): A TB patient whose biological specimen is resistant to isoniazid and susceptibility to rifampicin has been confirmed. 

 

Mono-resistant TB (MR TB): A TB patient whose biological specimen is resistant to one first-line anti-TB drug only. 

 

Multidrug-resistant TB (MDR-TB): A TB patient whose biological specimen is resistant to both H and R with or without resistance to other first-line anti-TB drugs. MDR-TB patients may have additional resistance to any/all FQ or any other anti-TB drug. 

 

Presumptive TB: This refers to a person with any of the symptoms or signs suggestive of TB. (Diagnosis of TB is difficult in certain key groups of the presumptive TB patients like extra- pulmonary, PLHIV, children, smear negative /NA with x-ray suggestive of TB, other vulnerable groups as defined in TOG-2016 and DR-TB contacts, hence, NAAT is offered upfront for diagnosis of TB among these presumptive TB patients).

 

Presumptive DR-TB: It refers to the patient eligible for rifampicin-resistant screening at the time of diagnosis OR/and during the course of treatment for DS-TB or H mono/poly DR-TB. [This includes all notified TB patients (Public and private), follow-up positive on microscopy including treatment failures on standard first-line treatment and H mono/poly DR-TB regimen and any clinical non-responder including paediatric].

 

Pre-extensively drug-resistant TB (Pre-XDR-TB): TB caused by Mycobacterium tuberculosis strains that fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone.

 

Poly-drug resistant TB (PDR-TB): A TB patient whose biological specimen is resistant to more than one first-line anti-TB drug, other than both H and R. 

 

Programmatic management of TB preventive treatment: PMTPT includes all coordinated activities by public and private health caregivers and the community to scale up TB preventive treatment to people who need it. 

 

Rifampicin resistant TB (RR-TB): A TB patient whose biological specimen is resistant to R was detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to R in the form of mono-resistance, poly-resistance, MDR or XDR. 

 

Serious adverse events: SAEs are those adverse events (AEs) classified as Grade 3 (severe), Grade 4 (life-threatening or disabling) or Grade 5 (death related to AE), or which led to the drug being stopped permanently. SAEs are otherwise often defined as AEs that lead to death or a life-threatening experience, initial or prolonged hospitalization, persistent or significant disability, or congenital anomaly. The management of SAEs may require termination of the drug suspected of having caused the event. 

 

Systematic screening for TB disease is a systematic identification of people with presumed TB disease in a predetermined target population, using tests, examinations, or other procedures that can be applied rapidly. (Among those screened positive, the diagnosis needs to be established by one or several diagnostic tests and additional clinical assessments, which together have high accuracy).

 

Tuberculosis (TB) is a disease that occurs in someone infected with M. tuberculosis. (It is characterized by signs or symptoms of TB disease, or both, and is distinct from TB infection, which occurs without signs or symptoms of TB. In this document, it is commonly referred to as “active” TB or TB “disease” to distinguish it from TB infection).

 

Tuberculosis infection (TBI) is a state of persistent immune response to stimulation by M. tuberculosis antigens with no evidence of clinically manifest TB disease. (There is no gold standard test for direct identification of M. tuberculosis infection in humans. Most infected people have no signs or symptoms of TB but are at risk for developing TB disease. TB infection is also known as “latent TB infection” (LTBI), although this term is being discarded given that infection cannot always be considered latent).

 

Tuberculosis preventive treatment (TPT) is offered to individuals who are at risk of developing TB disease to reduce that risk. (Also referred to as the treatment of TB infection).

 

Universal DST refers to universal access to rapid DST for at least Rifampicin (and where possible INH). It also includes DST for fluoroquinolones among all TB patients with Rifampicin resistance (preferably before initiation of treatment or as soon as possible).

 

Underweight: In adults and adolescents, underweight usually refers to a body mass index <18.5 kg/m2 and in children < 10 years to a weight-for-age < –2 z-scores.