Dissemination of MDR-TB and how molecular diagnostics can help
Tuberculosis (TB) is an airborne disease caused by an infection of the upper respiratory tract with Mycobacterium tuberculosis. Transmission occurs when airborne particles are expelled by infected individuals through coughing, shouting or sneezing.1 Tuberculosis is one of the top 10 causes of death worldwide and is the leading cause of death from a single infectious agent.2 In 2020, 33,148 cases of tuberculosis (7.3 cases per 100,000) were reported in 29 EU/EEA member states, and 2,287 cases of TB (3.8 cases per 100,000) were reported in Italy, down slightly from the previous year.3 According to the joint ECDC and WHO Europe document “Tuberculosis surveillance and monitoring in Europe 2022 (2020 data)”, between 2019 and 2020, there was a sharp decline in the number of notifications of new and relapsed cases of tuberculosis; this was partially due to a lower detection and underreporting of cases as a result of public health and social measures introduced in countries in response to the COVID-19 pandemic.3
The burden of drug-resistant tuberculosis
Isoniazid (INH) and rifampin (RIF) are the most effective first-line drugs used to treat the majority of people with tuberculosis.1 Other first-line drug treatments include ethambutol and pyrazinamide.1 Misuse of these drugs, including persistent suboptimal treatment, has led to drug-resistant, mono- or multidrug-resistant (MDR-TB) or extensively drug-resistant (XDR-TB) forms of tuberculosis.4
There are four main classifications for resistant tuberculosis:
- Monoresistant tuberculosis is the resistance to only one of the first-line antitubercular drugs, such as RR-TB.1
- MDR-TB is caused by microorganisms resistant to INH and RIF.1
- Extensively drug-resistant tuberculosis (XDR-TB) is a rare type of MDR-TB that is resistant to INH and RIF, as well as to any fluoroquinolone and at least one of three second-line injectable drugs (amikacin, kanamycin, or capreomycin ).1
- Pre-XDR-TB is tuberculosis caused by strains that meet the definition of RR-TB and MDR-TB and are also resistant to any fluoroquinolone.7
In 2019, 70,000 cases of RIF-resistant tuberculosis (RR-TB) and MDR-TB were reported in Europe. In 2020, 92% of microbiologically confirmed pulmonary TB cases notified in the European Region were RIF-resistant. Rifampicin-resistant or multi-resistant TB (RR/MDR-TB) was found in 34.3% of the pulmonary TB cases tested.3
Drug-resistant tuberculosis is harder to treat and more expensive, thus threatening the progress that has been made.5
It is estimated that over the next 35 years MDR-TB will cost the global economy $16.7 trillion.5 If current trends continue, MDR-TB could kill an estimated 75 million people worldwide by 2050.5 If not kept under control, models have estimated that over time the proportion of drug-resistant tuberculosis will continue to increase and become more difficult and more expensive to treat.5
Treatment of susceptible tuberculosis vs. treatment of drug-resistant tuberculosis
The four first-line drugs used to treat tuberculosis are RIF, INH, pyrazinamide, and ethambutol.6 They form the core of treatment regimens in the initial 6-9-month treatment phase and can be administered in different combinations.6 Reasons for failure of tuberculosis therapy include late diagnosis, the lack of timely and proper administration of effective drugs, less availability of less toxic and convenient drugs, extended treatment duration, non-adherence to drug regimen, and the evolution of drug-resistant strains of tuberculosis.6
Treatment for MDR-TB is usually longer (9 months or more) and consists of selected first-line drugs along with several combinations of second-line drugs, which when administered together are more expensive (≥ US $1000 per person) and increase toxicity.2 For these reasons, it is important that MDR-TB is correctly identified in order to determine the most effective and appropriate treatment. The WHO reported an overall success rate of 57% for the treatment of MDR-TB.2
Diagnostic tests for tuberculosis
The classic laboratory techniques used to diagnose tuberculosis, such as the direct microscopy, have low sensitivity (60-80%).⁸ Moreover, cultures require 2-8 weeks for bacterial growth, as well as biosafety precautions and trained laboratory personnel.⁸
Other diagnostic tests include immunological tests, which so far have shown limited performance, and serological tests, which are also limited in determining whether a person has had a previous tuberculosis infection and therefore cannot ascertain whether the person has an active tuberculosis infection.⁸
Efficient and accurate molecular diagnostics are a vital tool in diagnosing and guiding the treatment of MDR-TB for use in conjunction with conventional methods.12 The rapid reporting time of molecular testing aids patient management and the initiation of the appropriate same-day treatment. Furthermore, the molecular test can identify mutations in the genome of Mycobacterium tuberculosis (MTB)⁸, showing a very high sensitivity in sputum smear-positive patients and a sensitivity of about 61-76% in sputum smear-negative patients.⁹ The high sensitivity of the molecular test indicates that it is a more accurate diagnostic test than other conventional microscopic and immunological tests.
The WHO’s approval of NAATs
The current gold standard method for bacteriological confirmation of tuberculosis is still cultures using commercially available liquid media. However, in its updated tuberculosis operations manual, the WHO endorses more molecular tests based on nucleic acid amplification (NAATs).10 NAATs are recommended as initial diagnostic tests in order to minimise delays when it comes to initiating the appropriate treatment.10,12
For diagnostic testing in adults and children where there is suspicion of tuberculosis, the WHO states that countries should prioritise the use of rapid molecular testing over conventional microscopy, culture or drug susceptibility testing as an initial test to help ensure the availability of an early and accurate diagnosis.11
WHO-approved rapid diagnostic tests should be central to diagnostic work for all presumed cases of tuberculosis; the conventional microscopy should only be used as an initial diagnostic test in laboratory settings where rapid molecular tests are not available and if timely transportation of the specimen to a laboratory where these techniques are readily available is not possible.11
BD’s solutions for tuberculosis diagnostics
Thanks to its vast experience, from sample collection to the final result, BD guarantees its support to fully meet the needs of microbiology laboratories for genotypic and phenotypic TB testing and laboratory data management through computer software. This is all in line with what is stated in the newly updated AMCLI Diagnostic Pathway.12
Learn more about the BD MAX™ MDR-TB molecular test
Learn more about TB diagnostic solutions
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Bibliography
1. Centers for Disease Control and Prevention. Core Curriculum on Tuberculosis: What the Clinician Should Know.; 2021. Available at: https://www.cdc.gov/tb/education/corecurr/pdf/CoreCurriculumTB-508.pdf. Accessed October 27, 2021.
2. World Health Organization. Global Tuberculosis Report.; 2020. Available at: http://www.who.int/tb/publications/global_report/en/index.html. Accessed October 27, 2021.
3. Epicenter website. Tubercolosi: epidemiologia. https://www.epicentro.iss.it/tubercolosi/epidemiologia Visitato il 2 Dicembre 2022.
4. Centers for Disease Prevention and Control. Tuberculosis ( TB ) Drug-Resistant TB. 2021:1-4. Available at: https://www.cdc.gov/tb/topic/drtb/default.htm. Accessed October 28, 2021.
5. Tuberculosis WD. DRUG-RESISTANT TUBERCULOSIS: Worth the investment.; 2021. Available at: https://www.eiu.com/graphics/marketing/pdf/Drug-resistant-tuberculosis-Article.pdf.
6. Singh R, Dwivedi SP, Gaharwar US, et al. Recent updates on drug resistance in Mycobacterium tuberculosis. J Appl Microbiol 2020;128:1547-1567. Available at: https://onlinelibrary.wiley.com/doi/10.1111/jam.14478.
7. World Health Organisation. WHO announces updated definitions of extensively drug-resistant tuberculosis. WHO 2021;2015:1-2. Available at: https://www.who.int/news/item/27-01-2021-who-announces-updated-definitions-of-extensively-drug-resistant-tuberculosis. Accessed October 27, 2021.
8. Niemz A, Boyle DS. Nucleic acid testing for tuberculosis at the point-of-care in high-burden countries. Expert Rev Mol Diagn 2012;12:687-701. Available at: http://www.tandfonline.com/doi/full/10.1586/erm.12.71.
9. Nurwidya F, Handayani D, Burhan E, et al. Molecular Diagnosis of Tuberculosis. Chonnam Med J 2018;54:1-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/29399559.
10. World Health Organization (WHO). Consolidated Guidelines on Tuberculosis. Module 3 : Diagnosis -Rapid diagnostics for tuberculosis detection.; 2021.
11. WHO Regional Office for Europe. Algorithm for laboratory diagnosis and treatment-monitoring of pulmonary tuberculosis and drug-resistant tuberculosis using state-of-the-art rapid molecular diagnostic technologies.; 2017. Available at: https://www.euro.who.int/__data/assets/pdf_file/0006/333960/ELI-Algorithm.pdf. Accessed October 27, 2021.
12. AMCLI ETS. Percorso Diagnostico ” Tubercolosi” – Rif. 2023-18, rev. 2023″ https://www.amcli.it/wp-content/uploads/2023/05/18_PD_TUBERCOLOSI_def25mag23-2.pdf
