DR-TB HIV Coordinator: TB Diagnosis and Case Finding

National Tuberculosis Elimination Programme (NTEP) strives for all presumptive TB patients to be microbiologically confirmed. Under NTEP, the acceptable methods for microbiological diagnosis of TB are: 

Rapid diagnostic molecular test: Rapid molecular tests that use techniques like NAAT are very specific. They amplify the genomic material in the patient sample and hence enhances detection

• Nucleic Acid Amplification Test (NAAT) e.g., GeneXpert, TrueNat

  

  Figure: Genxpert Machine for CBNAAT

  

  Figure:  Truenat Machine

• Line Probe Assay

The two methods available for laboratory diagnosis of drug resistance/ susceptibility are as follows: 

Figure: Laboratory Diagnosis Methods: Drug Resistance Testing (DRT) and Drug Susceptibility Test (DST)

Resources

• Guidelines for Programmatic Management of Drug-resistant TB in India, 2021.

Cartridge Based Nucleic Acid Amplification Test (CBNAAT) is a rapid molecular diagnostic test. It is used for diagnosis of Tuberculosis (TB) and Rif-resistant Tuberculosis (RR-TB) in NTEP. Results are obtained from unprocessed sputum samples in about 2hours which helps in early detection and treatment of TB patients. 

India has vast number of CBNAAT laboratories which are utilized for TB/RR-TB detection and Universal Drug Susceptibility Testing (UDST) under the National TB Elimination Program (NTEP).  

Figure: CBNAAT Cartridge and Machine in Use (Image courtesy: USAID supported Challenge TB Project)

The CB-NAAT system detects DNA sequences specific for Mycobacterium tuberculosis complex and rifampicin resistance by Polymerase Chain Reaction (PCR). It concentrates Mycobacterium tuberculosis bacilli from sputum samples, isolates genomic material from the captured bacteria by sonication and subsequently amplifies the genomic DNA by PCR. The process identifies clinically relevant rifampicin resistance-inducing mutations in the RNA polymerase beta (rpoB) gene in the Mycobacterium tuberculosis genome in a real-time format using fluorescent probes called molecular beacons.

Video: Cartridge-Based Nucleic Acid Amplification Test [CBNAAT] - GeneXpert Technology 

Resources

• Training Module (1-4) for Program Managers and Medical Officers, NTEP, MoHFW, 2020.
• India TB Report 2021, National TB Elimination Program (NTEP), MoHFW, 2021.

Assessment Questions

Truenat is an indigenous rapid molecular test platform that is currently under use in NTEP for diagnosis of TB and Rif Resistance. It is a platform utilising real-time Polymerase Chain Reaction (PCR) technology built into micro-PCR chips.

Testing on Truenat involves three components:

1. Workstation (consisting of 2 devices)
   • Trueprep AUTO Universal Cartridge-based Sample Prep Device for the automated extraction and purification of DNA
   • Truelab Real-time micro PCR Analyzer for performing real-time PCR. It is available as 1 (Uno), 2 (Duo) or 4 (Quattro) chip ports.
2. Cartridge and Chip
3. Reagent kits (Sample Pre-treatment and Prep kits)

Figure: Truenat  Source: MolBio Products.

Test results for MTB detection and Rif Resistance has a turn around time of 1-2 hours. Depending on the micro-PCR chips used various tests can be performed using Truenat. Truenat MTB micro-PCR chips detect Mycobacterium tuberculosis bacteria for TB diagnosis. Truenat MTB RIF micro-PCR chip is used as a reflex test to detect resistance to Rifampicin (RIF), the first-line drug for TB treatment

Truenat has many advantages. Truenat is designed to be mobile and is battery operated (~8 hours on full charge). It can be deployed in peripheral laboratories and microscopy centres with minimal or no added facilities and hence it is more point-of-care. Biosafety requirements are similar to smear microscopy. However, it is multi staged and partially automated, requiring the presence of a Lab Technician through out the test.

Resources

1. Truenat MTB Kit Insert.
2. Trueprep AUTO Universal Cartridge-based Sample Prep Device.
3. Practical Guide to Implementation of Truenat Tests for the Detection of TB and Rifampicin-resistance, 2021.

Assessment

Line Probe Assay (LPA) is a rapid molecular test available at centralised laboratories.

The assay is based on Polymerase Chain Reaction (PCR) that can simultaneously detect Mycobacterium tuberculosis complex as well as drug sensitivity to anti-TB drugs.

Figure 1: The GenoType MTBDRplus Molecular LPA Procedure; Source: Molecular Detection of Drug-resistant Tuberculosis by Line Probe Assay.

Advantages of LPA

• Rapid molecular test. (Turnaround time: 3-5 days)
• Highly sensitive and specific.
• Performed directly from sputum smear-positive specimens and on isolates of M. tuberculosis complex grown from smear-negative and smear-positive specimens.
• Detects multiple gene mutations in anti-TB drugs.
  • First-line LPA detects mutations to rifampicin and isoniazid
  • Second-line LPA detects mutations to fluoroquinolones and aminoglycosides.
• Suitable for low and high-throughput labs.

Disadvantages of LPA

• Cannot be used as a point-of-care test.
• Requires appropriate laboratory infrastructure, equipment and biosafety precautions.
• Different rooms (DNA extraction, pre-amplification, amplification, post-amplification/ hybridization) are required to perform different steps (Figure 2).
• Requires trained manpower to perform tests and interpret test results.
• Stringent internal quality control is required to prevent contamination.

Figure 2: Amplification (A) and Post-amplification Laboratory (B) for LPA; Source: Molecular Detection of Drug-resistant Tuberculosis by Line Probe Assay.

Resources

• Guidelines for PMDT in India, 2021.
• Molecular Detection of Drug-resistant Tuberculosis by Line Probe Assay.

Assessment

Culturing TB Bacilli is well known and historic method for detection/ confirmation of Tuberculosis. It is a highly sensitive and specific phenotypic test; it can detect even a few viable bacilli in the sample (Upto 10 Colony Forming Units- CFUs). TB bacilli multiply in the culture and form colonies of TB bacilli which can are easily be identified.

Based on the growth media used Culture is divided in to two types, Solid and Liquid Culture methods. Types Culture:

• Solid Culture on Lowenstein Jensen media : Historic gold standard culture test. Results take usually upto 2 months (60 days).
• Modern Liquid culture systems: (e.g. BACTEC MGIT 960, BacT Alert or Versatrek etc.) Results take usually up to 42 days. 

Uses

1. Solid culture is the gold standard diagnostic test for TB. But it is not used for the purpose of TB diagnosis due to the long turn around time of 2 months. It is largely used for research purposes where it is used as the baseline test on which the sensitivity and specificity of other tests are calculated.
2. Liquid Culture is being used for follow-up monitoring of patients on drug resistant TB treatment to detect treatment failure. Liquid culture is also used for long term follow up patients who have successfully completed treatment to detect recurrence.
3. Liquid culture is used as a previous step to grow bacilli and obtain isolates prior to Drug Susceptibility Testing.
4. Liquid cultures are also used in TB prevalence surveys for its high sensitivity and specificity

Resources

• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India 2021

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Culture Drug Susceptibility Testing (CDST) is a growth-based phenotypic method used to check the susceptibility of Mycobacterium tuberculosis strains to various first and second line anti-TB drugs. Mycobacterial resistance to a particular drug is identified if there is growth observed in culture in presence of that drug.

In NTEP CDST is the standard method to detect resistance in samples of patients who have tested positive on followup. While CDST is possible on both Solid and Liquid culture, currently, the NTEP utilizes only liquid culture as a method for DST, due to faster Turn around times.

CDST testing services are available under NTEP in designated, specialized laboratories called CDST Labs both in public and private sector. Currently there are 80 such laboratories (60 certified for First Line and 49 for Second line drugs). Such designated laboratories are subject to regular external quality assessment, often by the National Reference Laboratory at that region.

Quality assured DST to R, H, Z, Mfx, Lfx, Lzd, Am, Km and Cm are available across the country. 

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, 2021.
• Training Manual for Mycobacterium tuberculosis Culture & Drug Susceptibility Testing, NTEP, 2009.
• RNTCP Laboratory Network Overview, CTD, 2009.

The concept of Patient Turnaround Time (P-TAT) is to find out how much time was taken from the identification of the patient for a test to getting the result of that test and initiation of patient's treatment based on the test result.

The National TB Elimination Programme (NTEP) have set benchmarks to monitor the P-TAT as provided in the table below. 

Programme officers/ staff needs to ensure that the P-TAT relative to the laboratory technology used, should be well within the minimum acceptable timeline as detailed in this table to improve patient treatment outcomes.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, March 2021.

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NTEP laboratory network is comprising of National Reference Laboratories (NRLs), state level Intermediate reference laboratories (IRLs), Culture & Drug Susceptibility Testing (C & DST) laboratories and peripheral level laboratories. Peripheral level laboratories consist of  designated microscopy centres (DMCs) and NAAT labs.

NTEP has a quality assured laboratory network for bacteriological examination of sputum in a 3-tiered system.

Figure: Laboratory network of NTEP

Resources:

• TB India Report 2021

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Under the National Tuberculosis Elimination Programme (NTEP), many labs are established at the regional level within states for providing Culture and Drug Susceptibility Testing (C&DST) facilities for presumptive TB/DRTB and for TB/DRTB patients. C&DST laboratories are mostly located in intermediate reference laboratories (IRLs) or medical colleges. There are 42 C&DST laboratories established under the programme in different geographies. Dedicated human resources are provided for the laboratories under the programme. Districts are linked with laboratories for providing facilities for Culture and DST using: Phenotypic Methods (Solid – Lowenstein Jensen (LJ), and Liquid Culture – Mycobacteria Growth Indicator Tube (MGIT)) Genotypic technology (Line Probe Assay (LPA) and Cartridge Based Nucleic Acid Amplification Test (CBNAAT))

Figure: Culture and Drug Susceptibility Testing (C&DST) facility, Source: The Foundation For Innovative New Diagnostics (FIND)

Resources

• Guidelines for Programmatic Management of Drug Resistant TB in India, 2021
• Training Modules (1-4) for Programme Managers and Medical Officers; New Delhi, India: Central TB Division, July 2020

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The National Tuberculosis (TB) Elimination Program (NTEP) has a network of Nucleic Acid Amplification Tests (NAAT) laboratories coupled with Designated Microscopy Centers (DMCs) to form the backbone of the diagnostic component of TB services.

Nucleic Acid Amplification Tests (NAAT) laboratories includes Cartridge-based NAAT (CBNAAT) and TrueNat tests. These tests detect tuberculosis as well as rifampicin resistance and are more sensitive than smear microscopy.

Functions of Nucleic Acid Amplification Test (NAAT) Laboratories:

1. Acting as a hub for collection of samples from public and private health facilities (spokes)
2. Universal Drug Susceptibility Testing (UDST) to rule out rifampicin resistance among confirmed TB patients
3. Timely provision of NAAT test result to the TB patient, medical officer of the concerned health facility and NTEP staff for related actions
4. Acting as a sample dispatch center for the Culture DST laboratory for subsequent processing of samples for first-line line probe assay (LPA) and second-line drug resistance testing utilizing second line LPA and liquid culture DST
5. Recording and reporting including digitization of diagnostic process from collection to test result in NTEP Nikshay portal and Laboratory Information Management System
6. Management of supplies and logistic associated with laboratory logistic (CBNAAT cartridges and TrueNAT chips) and reporting any additional requirement thereof
7. Supporting the quality assurance activities undertaken by District or Intermediate Reference Laboratory under NTEP
8. Support health system in carrying out special drives for vulnerable and at-risk population and their testing directly by CBNAAT (slum population, diabetic population, smoker, malnourished people, patients of silicosis and kidney dialysis etc.)

Resources

• RNTCP Technical and Operational Guidelines for TB Control in India, 2016.
• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India, 2021.

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Diagnostic services are provided free of cost at all public health laboratories, for patient referrals from the private sector. Laboratory services are also purchased from certified private sector laboratories through partnership schemes.

• The Initiative for Promoting Affordable and Quality TB Tests (IPAQT) was initiated in 2013 to bring World Health Organization (WHO)-approved tuberculosis tests at affordable prices to patients in the private sector. 
• IPAQT is an initiative of not-for-profit stakeholders and private sector labs/ hospitals (collection centres) with a pan-India presence. IPAQT brought together various private laboratories with the support of test manufacturers and other major stakeholders to:
  • Bring down the price for quality TB tests by up to 50% in the private sector (see table below)
  • Promote the use of these tests by building awareness among health providers, laboratories and patients

It's the responsibility of District TB Officers (DTOs) to ensure that, patients diagnosed through IPAQT laboratories are notified in the National TB Elimination Programme (NTEP) surveillance system and appropriate public health actions are initiated.

Resources

• Guidelines for Programmatic Management of Drug-resistant TB in India, 2021.
• IPAQT.

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Sputum microscopy diagnostic services under the National TB Elimination Programme (NTEP) are provided by the Designated Microscopy Centres (DMCs) established at the Peripheral Health Institution (PHI) level, where a functional binocular microscope and a trained Laboratory Technician (LT) is available. Light Emission Diode Fluorescent microscopes are provided to high-load PHI-DMCs such as that of the medical colleges. 

Based on latest directives, a DMCs may be established at all PHIs (Public and Private) of the country as needed. It is mandatory to have a DMC at all medical colleges in the country.

As molecular technologies like Truenat are also used in DMCs, NTEP has planned to rename DMCs as TB Diagnosis Centres (TDCs).

Criteria to be a DMC

The DMCs should satisfy the following criteria:

1. NTEP-trained Laboratory Technician (LT) should be present.
2. A functional binocular microscope should be present in the laboratory.
3. Physical infrastructure in the laboratory should meet NTEP guidelines.
4. Daily new adult outpatient cases of at least 60-100 and/or workload of at least 3-5 sputum smears per day for the LT in the laboratory.

DMCs in the public sector, at the onset of the programme, are provided with funds to undertake minor civil works to build up their physical infrastructure and are provided with binocular microscopes.

Human Resources Norms

• For the purpose of NTEP, a PHI is a health facility which is manned by at least a Medical Officer (MO).
• In addition to the MO and LT, there is 1 TB Health Visitor (TBHV) per one lakh urban population to support the urban TB control activities.

Other Criteria

Microscopy Centres may be established beyond population norms in medical colleges, corporate hospitals, Employee State Insurance Corporation (ESIC), railways, Non-government organisations (NGOs), private hospitals, Ayushman Bharat - Health and Wellness Centres (AB-HWCs), etc.

Before designating a DMC in other sectors, there should be a formal agreement by the hospital/ laboratory to take part in the External Quality Assurance (EQA) and to allow the concerned NTEP staff to supervise as per the NTEP guidelines.

If the above criteria are met by any private laboratory, the lab is considered for establishing a DMC.

• To provide better access for diagnosis of TB, all PHIs, wherever LTs and binocular microscopes are available, can be upgraded to a DMC irrespective of the population norms or OPD attendance.
• All DMCs should comply with the Quality Assurance (QA) mechanisms as per the EQA guidelines.

Resources

• NTEP Training Modules 1-4 for Programme Managers & Medical Officers, 2020.
• Operational Guidelines for TB Services at Ayushman Bharat Health and Wellness Centres.

Assessment Questions

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To increase access to diagnostic services, NTEP has a provision for sputum collection centres in areas where the health facility is not equipped with key requirements to conduct sputum microscopy, molecular tests, drug susceptibility testing or follow up examinations.

Sputum collection centres are dedicated locations where sputum samples are collected, packaged and then transported to nearby TB diagnostic centres. It could be attached to any near-by health-facility as well.

Requirements of a Sputum Collection Centre

To function as sputum collection centres, the following is essential:

• Linkage/ mapping (time and distance) to testing laboratory
• Availability of adequate number of sputum cups and falcon tubes, logistics for sample packaging and transport
• Identification of open areas for sputum collection
• Staff trained in NTEP guidelines on sputum collection, sample packaging and transport, complete and correct documentation of laboratory request form, and infection control practices
• Feasibility and financial measures required for sample transport
• Inclusion of local volunteers, courier services, sample transportation under National Health Mission Free Diagnostic Services or other mechanisms as decided by the state/district
• Availability of Information, Education and Communication (IEC) material, training modules, and job-aids
   

 Sputum collection centres are established in:

• Ayushman Bharat Health and Wellness Centres/Sub-centres
• Urban primary health centres
• Tribal, hilly, desert and difficult-to-reach areas of the country

Resources

• Training Modules for Programme Managers and Medical Officers
• Operational Guidelines for TB Services at Ayushman Bharat Health and Wellness Centres
• Mycobacteriology Laboratory Manual, GLI Initiative, 2014

Assessment:

• Good quality sputum collection is of paramount importance in tuberculosis diagnosis.
• Once a person is identified as presumptive TB, s/he is referred to the Designated Microscopy Centre (DMC) for sputum collection.
• For TB diagnosis two sputum samples are collected - one is the supervised ‘spot’ sample collected at the DMC (labelled Specimen A) and the other is the early morning sample collected by patient themselves at his/her home (labelled Specimen B).
• If the patient is coming from a long distance or s/he is unlikely to return to give the second specimen, two spot specimens may be collected with a gap of at least one hour.

Figure: Flowchart for Sputum Collection and Transport

Sputum Collection

• The (NTEP) request form required for the biological specimen examination need to be filled.
• The Lab Technician (LT) should instruct the patient to thoroughly rinse the mouth with clean water and demonstrate to inhale deeply 2-3 times and cough out the sputum from the depth of the chest into a sterile 50 ml sputum container, in a well-ventilated space.
• After collecting the sputum, close the lid of the containers and wipe the surface of the tube with 5% phenol to disinfect and allow it to air dry.
• Label the tubes with patient details, date and time of collection, specimen identification, lab no. using a permanent marker.

Sputum Transport

• The sputum collected should be transported immediately to the Nucleic Acid Amplification Testing (NAAT)/ Culture and Drug Susceptibility Testing (C&DST) laboratory. In case of any unavoidable delays, the sample should be refrigerated.
• The programme mandates triple layer packaging for the transport of the sputum specimens.
• Firstly, seal the joint between the cap and neck of the sputum containers with a parafilm strip (primary receptacle package).
• Wrap the sputum containers individually in absorbent cotton, place them in a zip lock pouch and secure them with a rubber band (secondary receptacle package).
• Fold and place the NTEP request form in another zip lock pouch.
• Place the zip lock pouch with sputum containers in a thermocol box along with two pre-frozen coolant gel packs and the zip lock pouch with the NTEP request form is placed on top.
• The dimensions of the thermocol box used for sputum transport are: thickness - 2.5 cm; Outer dimensions: length - 18.5 cm, breadth - 13 cm, height - 12 cm (without lid), height -14 cm (with lid); Inner dimensions: length - 14.5 cm, breadth - 8 cm, height - 12 cm (without lid), height - 13 cm (with inner part of lid).
• The coolant gel packs should be conditioned in the deep freezer in a temperature between -20 to -15^o C for a minimum 48 hours to a maximum 72 hours before use so that they can maintain a temperature between 12-20^o C for up to approximately 48 hours in tightly packed thermocol boxes while the average outside temperature is 35^o C. 
• Seal the thermocol box with duct tape and affix ‘To’ and ‘From’ address, biohazard sticker on the box (tertiary receptacle package).
• Weight of the fully packed consignment box should be up to 400 grams and the thermocol boxes and gel packs should not be reused. 
• Transport the box through NTEP identified courier/ speed post service.

Resources

• Training Module (1-4) for Programme Managers and Medical Officers, NTEP, MoHFW, 2020.
• Guidelines for Programmatic Management of Drug-resistant TB in India, 2021.
• Module for Laboratory Technician, CTD, MoHFW, India, 2005.

Assessment

Screening for active tuberculosis (TB) a process to filter out people who are less likely to have TB, from a group. Screened positive people are likely to have TB and are confirmed subsequently using a TB diagnostic test. This will allow finite diagnostic testing resources to be used on the remaining.

Screening in TB may be performed ​using simple field tools (4 Symptom complex) and tests such as Chest X-ray, or a combination of both. ​Combination of both is the most effective, but is often not applied due to the practical difficulties in making a chest X-ray conveniently available.

Screening is an integral part of any general case finding effort. It is also applied systematically in specific situations.

1. At health care facilities (intensified case finding): Here those visiting are screened using the 4 symptom complex, often at the point of entry to the facility. Those screened positive may be fast-tracked to TB Diagnostic testing.
2. In vulnerable populations in active case finding efforts: Here the entire population identified for active case finding are screened using the pre-decided protocols by going door to door. 

Resources

• Systematic Screening for Active Tuberculosis; Principles and Recommendations, WHO 2013.
• National Strategic Plan for Tuberculosis Elimination 2020–2025.

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.    

• Universal Drug Susceptibility Testing (UDST) refers to universal access to rapid DST for at least Rifampicin (R), and further DST for at least Fluoroquinolones (FQs) among all TB patients with rifampicin-resistance.
• UDST is essential to identify patients who can be initiated on Drug-resistant TB (DR-TB) treatment instead of Drug-sensitive TB (DS-TB) treatment, especially in a situation where the drug-resistance level is high.
• It should be done preferably before initiation of treatment to a maximum within 15 days of diagnosis.
• UDST is a part of national policy under the National TB Elimination Programme (NTEP).
• NTEP has undertaken decentralization of quality assured diagnostics for scale up of UDST across the country which has helped in early detection of DR-TB treatment and reducing associated morbidity and mortality. 

Resources​
 

• Guidelines for Programmatic Management of Drug-resistant TB in India, 2021.

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Video: UDST Report

People who have been exposed to patients with infectious TB are known as TB contacts; they constitute a high-risk group for TB. Case finding investigation contributes to the early detection of TB cases, and results in identifying a significant number of additional patients.

Figure: Approaches to Tuberculosis Case Finding

Active case-finding requires systematic screening and clinical evaluation of populations who are at high risk of developing TB, such as people living in slums, tribal areas, congregate settings, persons who are household contacts of TB cases

Resources:

• Assessing TB Case-Finding

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Systematic screening of all individuals of a defined population is known as active case finding.  It is applied outside of health facilities at the community level by the health system.

Objective of ACF is to:

1. identify cases early, initiate prompt treatment, reduce risk of poor treatment outcomes and reduce risk of further transmission of TB
2. to provide access to diagnosis services to populations that would have been otherwise unreached

It is effort intensive and is recommended only in population groups where there is estimated high case load. In NTEP, ACF is recommended only to be performed in Key / vulnerable population.

ACF can also be clubbed with suitable ACSM campaigns to create awareness about the signs and symptoms and about TB in the target population/ community. It can also be combined with other health activities/ campaigns (such as Pulse Polio/ Leprosy screening/ population based screening for NCDs) for increased efficiency.

Resources

1. Training Modules for Programme Managers and Medical Officers.
2. Active TB Case Finding, Guidance Document.
3. WHO recommendations for Systematic Screening for Active Tuberculosis

Assessment

Passive case finding is essentially where the patient self reports to the health care provider with symptoms. This requires that affected individuals are aware of their symptoms, have access to health facilities, and are evaluated by health workers or volunteers who recognise the symptoms of TB and link those individuals for TB testing services.

This approach to case finding has the least effort and cost and is a minimum expectation. In a Peripheral Health Institution (PHI), it is estimated that about 2-3% of new adult outpatients are symptomatic that require referral for TB diagnosis (presumptive TB cases).

Passive case finding may miss TB patients if :

1. The disease is mild/ transient.
2. Access to healthcare is poor.
3. Health providers do not have an adequate index of suspicion and are unable to reliably link respiratory symptoms to TB. 

Resources

1. Training Modules for Programme Managers and Medical Officers.

Assessment

Intensified Case Finding (ICF) is a case finding approach between Active and Passive approaches. Here individuals coming in contact with the health system through any activity are screened actively for symptoms of TB and referred for testing.

This approach brings the benefit of active case finding approach by active screening for TB symptoms, but does limit the extensive effort required by restricting to only those people who has some or the other healthcare problem. This approach is considered for people attending a healthcare facility.

Some examples of ICF are screening for TB symptoms and referral for testing in:

• all cases attending an HIV clinic.
• among children with malnourishment who attend a nutrition clinic.
• all mothers attending the antenatal clinics

Resources

1. Technical and Operational Guidelines.
2. Assessing TB Case Finding.

Assessment

Bidirectional screening is a method to identify cases in diseases which have predisposition to each other or has a significant influence on each other. For example TB and HIV, where having HIV increases risk of developing TB and cases with TB would have poor outcomes if co-infected with HIV.

Screening for TB is done through four-symptoms complex based screening or through Chest X-ray. Screening for the linked disease is carried out as per the policies of the corresponding health program.

Bi-directional screening policies are implemented by various disease control programs. For example, with NTEP the following disease control efforts implement a bidirectional screening policy:

1. HIV through NACO 
2. COVID19 
3. Diabetes Mellitus (DM) through NPCDCS
4. Tobacco  through National Tobacco Control Program

Both programs monitor bidirectional screening, referral and testing as per their own policies.

Resources

1. National Strategic Plan for TB Elimination.

Assessment

Why important, how is it done,

Persons with cough of more than 2 weeks, with or without other symptoms suggestive of TB, should be promptly identified as presumptive pulmonary TB patients.

Under NTEP, they are to be referred to the designated microscopy centre (DMC) for sputum examination using the Request form for examination of biological specimen.

Patients belonging to the key population EPTB, HIV and Paediatrics groups (after X-ray screening in case of children) can be directly referred for NAAT.

All presumptive TB patients in the public and private sector must be evaluated for TB based on the diagnostic algorithm for pulmonary and extra-pulmonary TB (EPTB) and the following points must be considered:

• All presumptive pulmonary TB patients must be subjected to sputum smear examination. In places where TB diagnostic laboratories are upgraded to NAAT testing, NAAT can be offered for all presumptive TB patients upfront
• If both the chest X-ray and sputum smear (NAAT in integrated places) results are negative, but the physician considers the patient as presumptive TB, the patient needs to be referred to a chest physician for further evaluation
• NAAT testing will be performed to rule out Rif. resistance before treatment initiation (In places where transition has not yet been happened to NAAT for diagnosis)
• NAAT results will decide if the patient is MTB detected with either Rif. Resistance or Rif. Sensitive
• Upfront NAAT is offered for key populations like PLHIV/children/EPTB
• M.TB detected on NAAT will be further subjected for FL–LPA, SL-LPA, LC DST and based on the results DR-TB regimen may be initiated

Resources

• Technical and Operational Guidelines for TB Control in India 2016
• Revised PMDT Guidelines in India 2021

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It is crucial to make an effort for microbiological confirmation in presumptive Extrapulmonary Tuberculosis (EPTB) cases. Appropriate specimens from the Extrapulmonary (EP) site are collected and, depending on the specimen type and availability of facilities, the specimens are sent for:

• Cartridge-based Nucleic Acid Amplification Testing (CBNAAT)
• Culture and Drug Susceptibility Testing (C&DST) for M. tuberculosis 
• Histopathological examination

The diagnostic algorithm (see the figure below) to be followed for EPTB cases depends on 2 main factors:

1. Availability of appropriate specimens from the EP site
2. Availability of CBNAAT (preferred test)

Figure: Diagnostic Algorithm of EPTB

• If an appropriate specimen from the EP site is available, specimens from the presumed sites of involvement must be tested with CBNAAT.
• CBNAAT detects MTB and RIF status and helps to identify microbiologically confirmed EPTB cases.
• If CBNAAT is not available, the specimen is sent for Liquid Culture (LC) at the C&DST lab. If the LC is positive, it is identified as a microbiologically confirmed EPTB case.
• If there is high clinical suspicion of TB even after a negative culture result, other diagnostic tools are used to clinically diagnose EPTB (usually with a specialist). If these tests indicate TB, they may be treated as clinically diagnosed EPTB or else arrive at an alternate diagnosis.

Clinical Diagnosis of EP-TB

If an appropriate specimen from the EP site is not available, in the presence of high clinical suspicion of TB, other modalities of diagnosis are used in consultation with a specialist. If with other diagnostic modalities, TB diagnosis still cannot be established, the specialist may explore an alternate diagnosis. 

A clinical diagnosis of EPTB is made if a consultative decision is made to treat with a full course of anti-TB drugs in spite of the situations listed above. Chest X-ray (CXR), ultrasonography, Computerised Tomography (CT) scan, Magnetic Resonance Imaging (MRI) and biochemical examinations are supporting tests that can be used to help arrive at a diagnosis.

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Technical Operational Guidelines, Chapter 3: Case Finding and Diagnosis Strategy, NTEP.

Assessment

​

All children with persistent fever with/without cough for two or more weeks; close contact with TB patients in the last 2 years; unexplained sudden weight loss or signs of malnutrition despite good nutrition, should be subjected to Chest X-ray (CXR).

1) If the CXR is normal, the child should be checked for signs of Extrapulmonary TB (EPTB) and referred for detailed investigations to higher centres in case of any symptoms.

2) If the CXR is suggestive of TB, the child should be subjected to a sputum test/ gastric aspiration / induced sputum for Mycobacterium tb (MTB) testing.

               - If the report is MTB positive, the child is microbiologically confirmed for TB and should be further tested for Rifampicin (Rif)-resistance and treated accordingly for Drug-sensitive (DS)/ Drug-resistant (DR) TB, based on Rif results.

               - If the report is MTB negative, look for significantly enlarged peripheral lymph nodes and also repeat the sputum test with a good sample and refer to a higher centre if required.

3) If the CXR displays non-specific shadows prescribe antibiotics (amoxiclav/ amoxicillin) if not already taken. Do not prescribe quinolones or linezolid and review the shadow and symptoms.

4) If CXR displays pleural effusion send the pleural fluid for examination at Nucleic Acid Amplification Testing (NAAT) lab as well for cytology and biochemical examinations.

              - If pleural fluid turns out MTB positive at the NAAT, treat as per guidelines

              - If the pleural fluid is MTB negative, but is a straw-coloured exudative effusion, treat the child as clinically diagnosed probable TB.

Image

Figure: Diagnostic Algorithm for Paediatric TB; Source: Standard Treatment Workflows of India: Special Edition on Paediatric and Extrapulmonary Tuberculosis, 2022.

Resources

• Standard Treatment Workflows of India: Special Edition on Paediatric and Extrapulmonary Tuberculosis, ICMR, MoHFW, GoI, CTD, 2022.
• Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India, CTD, MoHFW, GoI, 2021.

Assessment

Drug-resistant TB (DR-TB) diagnosis is predominantly based on laboratory diagnosis. Presumptive-TB/ DR-TB is identified by the health facility doctor during passive screening or by health staff/ community volunteers during Active Case Finding (ACF). 

The vision of National TB Elimination Programme (NTEP) is to provide early diagnosis to all persons with any form of DR-TB through Universal Drug Susceptibility Testing (UDST).

All diagnosed TB patients are eligible for a NAAT test to know their Rifampicin sensitivity status. The integrated diagnostic algorithm for diagnosis of TB offers upfront Nucliec Acid Amplification Test (NAAT) for diagnosis of TB to vulnerable population. Among other eligible groups for NAAT are: non-responders to treatment and contacts of DR-TB patients are also offered upfront NAAT.

Rapid identification of DR-TB is achieved by using a combination of NAAT (CBNAAT/ Truenat) followed by sequential testing by first- and second-line Line Probe Assay (LPA) and Liquid Culture (LC) and Drug Susceptibility Testing (DST) for specific drugs as described below:

• When Rifampicin resistance is not detected by NAAT, the patient is offered First-line (FL) LPA.FL-LPA provides information on Isoniazid resistance.
• For Rif resistance/Inh resistance cases, SL-LPA  is done and it provides information on resistance to Levofloxacin, Moxifloxacin and Amikacin.
• For all Rif resistance cases, LC and DST is done for Pyrazinamid, Moxifloxacin (if resistance detected by LPA), Linezolid, Clofazimine*, Bedaquiline* and Delamanid*.

(* when available)

Resources

• Guidelines for PMDT in India, 2021.

Assessment

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Presumptive Drug-resistant TB (DR-TB) in Children

It occurs mostly in children who:

• Are contacts of adults with Multidrug-resistant (MDR)/ DR-TB
• Are lost to follow-up after initiating treatment
• Present with recurrence of disease after previous treatment
• Do not respond to treatment with first-line drugs
• Are Children Living with HIV (CLHIV).

All efforts must be taken to ensure microbiological confirmation of DR-TB diagnosis among children through getting an appropriate body fluid sample for both pulmonary or extrapulmonary-TB cases.

Sputum (or other relevant samples, e.g., gastric aspirate, induced sputum, bronchoscopic lavage, lymph node aspiration, Cerebro Spinal Fluid (CSF), tissue biopsies) needs to be collected in all children with presumed DR-TB for diagnosis.

The diagnosis of DR-TB in children is done based on Nucleic Acid Amplification Test (NAAT) or Line Probe Assay (LPA) results. If these are invalid, Culture and Drug Susceptibility Testing (C&DST) will be carried out to establish the diagnosis.

In a presumptive DR-TB patient, if there is no bacteriological confirmation, bacteriologically negative clinically diagnosed probable DR-TB can be considered after ruling out alternative diagnosis.

Resources

• Guidelines for Programmatic Management of Drug-resistant Tuberculosis in India, 2021.

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All childhood TB patients’ sputum and other relevant samples (e.g. gastric aspirate, induced sputum, bronchoscopic lavage, lymph node aspiration, CSF, tissue biopsies etc.) should be subjected to genotypic or the phenotypic Drug Susceptibility Tests (DSTs). Based on the bacteriological confirmation, the child should be treated for DS/DR TB as required.

But in cases where the child’s DST is unknown, the source patient’s DST should be considered.

If the source is a known DS TB, treat the child for DS TB. If the child responds poorly to the DS TB treatment consult the pediatrician and re attempt the necessary investigations.

If the source patient is a known DR TB patient, consult with the pediatrician and re-attempt DST on an appropriate specimen from the child and treat as per the child’s DST (if the report is conclusive), if not then treat the child as DR TB after the source patient.

If the source patient’s DST status is not known perform DST on the child’s and the source patient’s specimen and treat the child as per the DST of the child or the source patient, whichever report is conclusive.

Pediatric TB patients should be presented to and discussed with a DR-TBC Committee (including the pediatrician) to decide the treatment.

Image

Figure:  Diagnostic Algorithm for Paediatric DR-TB; Source: Guidelines on Programmatic Management of Drug-resistant TB (PMDT) in India,2021, CTD, MoHFW, India, p39. 

Abbr: DR-TB: Drug-resistant TB; DS-TB: Drug-sensitive TB; NAAT: Nucleic Acid Amplification Test; MGIT: Mycobacterium Growth Indicator Tube; DST: Drug Susceptibility Testing; DRT: Drug Resistance Testing; BAL: Bronchoalveolar Lavage.

Resources

• Standard Treatment Workflows of India: Special Edition on Paediatric and Extrapulmonary Tuberculosis.

• Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India, 2021, CTD, MoHFW, India.

Assessment

Based on the site of disease, Tuberculosis can be classified as-

1. Pulmonary tuberculosis (PTB) refers to any microbiologically confirmed or clinically diagnosed TB involving the lung parenchyma or the tracheo-bronchial tree.
2. Extra Pulmonary tuberculosis (EPTB) refers to any microbiologically confirmed or clinically diagnosed TB involving organs other than the lungs such as pleura, lymph nodes, intestine, genitourinary tract, joint and bones, meninges of the brain etc. 

Note: Miliary TB is classified as PTB because there are lesions in the lungs. A patient with both pulmonary and extra-pulmonary TB should be classied as a case of Pulmonary TB.

• New case - A TB patient who has never had treatment for TB or has taken anti-TB drugs for less than one month is considered as a new case. 
• Previously treated patients have received 1 month or more of anti-TB drugs in the past. They could be further classified as:
• Recurrent TB case - A TB patient previously declared as successfully treated(cured/treatment completed) and is subsequently found to be microbiologically confirmed TB case is a recurrent TB case. 
• Treatment After failure patients are those who have previously been treated for TB and whose treatment failed at the end of their most recent course of treatment.  
• Treatment after loss to follow-up A TB patient previously treated for TB for 1 month or more and was declared lost to follow-up in their most recent course of treatment and subsequently found microbiologically confirmed TB case 
• Other previously treated patients are those who have previously been treated for TB but whose outcome after their most recent course of treatment is unknown or undocumented. 
• Transferred In: A TB patient who is received for treatment in a Tuberculosis Unit, after registered for treatment in another TB unit is considered as a case of transfer in.
• Transferred Out : A patient who has been transferred to another recording and reporting unit and whose treatment outcome is unknown.

Resources:

• Guidelines for Programmatic Management of Drug Resistant Tuberculosis in India, March 2021 
• WHO Consolidated Guidelines on Tuberculosis: Module 4-Treatment: Drug resistant TB Treatment, 2020

On the basis of diagnosis, Tuberculosis (TB) can be classified into 2 main types:

1. Microbiologically confirmed TB
2. Clinically diagnosed TB

Microbiologically Confirmed TB

• Microbiologically confirmed TB refers to a presumptive TB case from which a biological specimen is positive for acid-fast bacilli/ Mycobacterium tuberculosis on smear microscopy, culture, or on a rapid diagnostic molecular test (such as Cartridge-based Nucleic Acid Amplification Test (CBNAAT)/ Truenat).
• All such diagnosed cases should be notified at the source, regardless of whether TB treatment has started.

Clinically Diagnosed TB

• Clinically diagnosed TB refers to a presumptive TB case that is not microbiologically confirmed but has been diagnosed with active TB by a clinician who has decided to give the patient a full course of anti-TB treatment.
• This definition includes cases diagnosed on the basis of X-ray abnormalities or suggestive histology or extrapulmonary cases without laboratory confirmation.
• Clinically diagnosed cases subsequently found to be microbiologically positive (before or after starting treatment) should be reclassified as microbiologically confirmed.

Resources

• Training Modules (1-4) for Programme Managers and Medical Officers, 2020.
• Definitions and Reporting Framework for Tuberculosis, WHO, 2013.

Assessment