Yes, you heard it right. it is estimated that bacteria causing tuberculosis may have been around as long as 3 million years. Tuberculosis in humans can be traced back to around 9000 years, as found in the remains of a mother and child buried together (mummies) in Altit Yam, (a city now submerged in the Eastern Mediterranean Sea)². 

The first written document of Tb in humans is found in India around 3300 years ago²

Tuberculosis was known by many names until 1834 when Johann Schonlein coined the term “tuberculosis”². On 24th March 1882, Robert Koch discovered the bacteria causing tuberculosis. Now 24th March is designated as ‘World TB Day’ to spread awareness about the disease. Until the elimination of TB, World TB Day won’t be observed as a celebration.

You may be surprised to know that TB was the biggest killer among all infectious diseases until the covid-19 had appeared. As we know that COVID-19 has been declared as not a public health concern of international importance, TB will top the list again. 

According to WHO around 1 crore 6 lakh people fell ill with Tuberculosis and 16 lakh people died from Tuberculosis in 2021. Most of them who died belong to low- and middle-income countries (LMIC)3

Why are we struggling with Tuberculosis?

A number of factors may be held responsible. Some are attributed to the disease-causing bacteria and some to the strategies used to eliminate (cases of TB less than 1 per million population).

As we know three major arms to control a disease are prevention, diagnosis, and treatment. Diagnosis of Tb has remained the weakest part in controlling/eliminating the Tb. absence of an effective vaccine and a long treatment period are the other factors.

Let’s talk about the challenges in diagnosing Tuberculosis.

Challenges in Diagnosing Tuberculosis

Every improvement in the treatment strategies shall remain futile unless a diagnosis of the disease is made. Early diagnosis not only improves the chances of a complete cure but also prevents the disease’s spread.

Let’s have a look at the challenges and the way out possible:

Age-old sputum sample to diagnose tuberculosis

• Mystery client (standardized patient) studies in several countries have reported that primary care providers are reluctant to order microbiological tests during initial consultations¹.patient is offered the empirical antibiotic treatment rather than microbiological sputum testing.

• Even a sizeable number of presumptive tuberculosis patients are not able to produce the sputum.
• When samples are easy to obtain, providers are more likely to order diagnostic tests.

Way out possible:

1. development of non-sputum-based assays for screening or diagnosing tuberculosis.

non-sputum specimens like urine or oral or tongue swabs shall be more convenient for both patient and health care provider. The good news is that the research is on and soon we may have such non-sputum diagnostics satisfying WHO guidelines¹

2. Developing handheld portable and affordable digital X-ray systems backed with artificial intelligence (as used in Una district of Himachal Pradesh, India) could show a huge impact. Cough and lung sound recordings are being explored as digital biomarkers for TB screening. 

Over-reliance on microscopy

Though cheap and widely available it suffers a number of limitations

• The sensitivity is low
• the outcome is operator-dependent and requires the complex quality assurance of microscopy
• requires a quality specimen of sputum.
• can’t comment on antibiotic sensitivity 
• extra-pulmonary tuberculosis can’t be diagnosed

way out possible: Molecular testing

1. Molecular testing is more accurate and detects drug resistance. WHO recommends molecular tests as an initial diagnostic test.
2. Muti disease testing is possible in molecular testing strategies.

Therefore we should work to replace sputum smear microscopy with approved molecular testing. The need for the hour is to expand the molecular testing capacity as we did in COVID-19 testing.

Decentralization of testing:

As we developed single-use, molecular self-tests for COVID-19, we observed a spike in the testing. In the same way, if we can develop such testing options at the individual level or at least at the primary health care level, we can diagnose the patients much earlier and thus control tuberculosis more efficiently.

Affordability of test

The test should be affordable. Even if offered for free to patients, somebody is to bear the cost. It is therefore important to transfer the technology and diversification of manufacturing. There is a need for a transition from high-cost, low-volume products made in high-income countries, to more affordable, lower-cost, higher-volume products made in LMICs. When the test is affordable it shall be used initially and widely to detect tuberculosis early in the course of the disease. 

Targeting the populating diagnostic yield:

A test that is capable of reaching a much larger population can be very useful even if less sensitive. This can be understood by the example of the rapid syphilis test which although less sensitive than conventional lab assays but its greater coverage has helped maternal health program in testing and treating pregnant women¹.

Finances for Research and developments

2 million USD (United States dollars) are required worldwide for research and development purposes every year. But we were able to manage even less than half of it ( 0.9 million USD) during 2021⁴. for the development of better diagnostic tests and effective vaccines against tuberculosis, research and development is the most important step and it can’t be ignored.

Why Treatment of Tuberculosis Spans Over Months

We know that tuberculosis requires multidrug and long-term treatment spanning over 6 months to 2 years depending upon the resistance to drugs. There are 2 main mechanisms by which tuberculosis bacteria develop resistance which requires prolonged and multi-drug treatment of the disease:

1. Genetic resistance– fixed and heritable. Greater the number of bacteria more the chances of mutant or genetic resistance. When the therapy is administered inadequately the susceptible bacteria die out but resistant or mutant bacteria grow and lead to treatment failure. It is therefore advised to use multiple drugs to cover all the strains.
2. Phenotypic resistance– reversible resistance means resistance is present in a non-dividing dormant state but susceptible to the same drugs in a dividing or active state. Usually shown by the subpopulation of bacteria that do not replicate or multiply until the anti-tubercular drugs are administered and escape the drug by phenotypic resistance. Once the drug is stopped they start to grow and divide and cause a relapse of the disease. Long-term treatment of disease cures the patient because bacterial populations periodically leave the non-diving state and divide actively and are thus destroyed by the drugs.4

Based on the above discussion it is clear that the development of antibiotics effective against the non-dividing bacteria is of prime importance that can help shorten the treatment duration.

Why has vaccine not been developed so far

Though the BCG the only vaccine used against tuberculosis is available, it has a number of issues associated as the efficacy of the vaccine is variable and depends upon a number of factors like- geographic location, genetic variability in the population, strains of bacteria used in the vaccine etc. BCG vaccine is not used in developed nations having a low burden of active tuberculosis.

An effective Vaccine if developed can be a game changer but there are many reasons that vaccine development has not been possible so far. Tuberculosis bacteria along with humans have evolved over thousands of years. It has gained the ability to escape both host response and exogenous drug attack. It uses the safe heavens in the host cell which are primarily to protect the body from infections. like using alveolar macrophages to escape the host and drug attack. The molecular mechanism is very complex and the exact mechanism requires a lot of research and development. 

Currently, there are more than 16 vaccine candidates being evaluated in the clinical trial and soon we may have the one but requires a continuous focus on R&D and financial resources to support it.

References:

1. Daniels, B., Kwan, A., Pai, M. & Das, J. J. Clin. Tuberc. Other Mycobact. Dis. 16, 100109 (2019). (from Pai, M., Dewan, P.K. & Swaminathan, S. Transforming tuberculosis diagnosis. Nat Microbiol 8, 756–759 (2023). https://doi.org/10.1038/s41564-023-01365-3.Published 01 May 2023. Issue DateMay 2023.DOIhttps://doi.org/10.1038/s41564-023-01365-3)
2. https://www.cdc.gov/tb/worldtbday/history.htm
3. World health organisation
4. https://www.who.int/news-room/fact-sheets/detail/tuberculosis#:~:text=Tuberculosis%20(TB)%20is%20an%20infectious,been%20infected%20with%20TB%20bacteria.