New Developments, Interventions In TB Diagnosis & Treatment
WHO recommends that the initial method for confirmation of TB should be molecular (which would detect between 16 and 131 bacteria in the sample) rather than AFB (Acid Fast Bacilli) smear examination, which needs at least 10,000 bacteria to be present in the sample
Tuberculosis (TB) is a disease of great antiquity. Evidence of human infections has been found in mummies dating 9000 years back. Initially, it was thought to be hereditary, but it's microbiological origin was first described on 24th March 1882 in Germany by Robert Koch, a general physician. With the discovery of Streptomycin, it was hoped that TB would be wiped out.
Instead, TB now has become a tremendous public health problem, especially in developing countries. More people have died from TB (1 billion) than any other disease, thus becoming a public health emergency.
In 2015, World Health Organization got all heads of state to agree that the time had come to shift focus from control of TB to eradication. Several advancements have occurred since the new emphasis on eliminating TB as a public health problem by 2035 with political will and matching funds. WHO has released a new set of consolidated guidelines. Covid-19 has led to a setback, but eradication efforts are back on track.
Though TB can affect any part of the body, pulmonary TB is the most typical manifestation of the disease since it is transmitted through the respiratory route. The gastrointestinal route from infected cows had been blocked by our ancestors’ habit of boiling milk before drinking, later by pasteurization in the west.
Cough, low-grade fever, night sweats, and weight loss are the four cardinal symptoms of TB; anyone experiencing these for more than two weeks should seek medical attention. Recently artificial intelligence software has been developed to read digital chest X-Ray and detect hot spots in the lungs, making them suitable for mass active case finding of TB in the community.
People who are either symptom positive or have hot spots in AI read digital chest X Rays should be confirmed to suffer from TB by examining their sputum. A spot sample should always be collected. An early morning sputum sample, representing six to eight hours of secretion collection in the bronchial tree, might also be tested in the early stages.
WHO recommends that the initial method for confirmation of TB should be molecular (which would detect between 16 and 131 bacteria in the sample) rather than AFB (Acid Fast Bacilli) smear examination, which needs at least 10,000 bacteria to be present in the sample before it can be detected by smear microscopy.
The consequence of using smear microscopy, which is easy to perform and cheap, is that it would take at least six months before the bacterial load crosses the detection level. Still, since 3 bacteria can transmit infection, the person would infect 5 to 25 close contacts before being put on treatment.
The government has made molecular methods, Cartridge based nucleic acid amplification test (CBNAAT), or Truenat free of cost in every part of the country. Clinton Foundation, through IPAC, has made these tests available in private laboratories at fixed prices.
CBNAAT, also called Gene Xpert, detects both Mycobacterium tuberculosis complex (MTBC) and reports on susceptibility to Rifampicin, which has been used as a surrogate marker of Multidrug Resistance (MDR) TB, indicating both INH and Rif resistance.
Results take only two hours of machine time, so reports should be available for decision-making by the next day. Drug Susceptible TB (DS TB) would be treated with four drugs for two months, followed by two for four. All drugs are made available free of cost to the patient.
However, the long duration of treatment has led many persons to discontinue the treatment midway, which allowed the damaged bacteria not only to recover and continue the infection but also to become drug resistant. In the past, clinicians used a number of regimens for varying lengths of time, leading to MTBC becoming resistant to many anti-TB drugs. If the MTBC resists INH and Rif, it is called MDR TB.
If, in addition, it is resistant to fluoroquinolones, aminoglycosides were called XDR TB (extremely drug resistant). It, therefore, came as a new ray of hope when reports from South Africa emerged that using three all oral drugs, Bedaquiline, Linezolid, and Protionamide, researchers could cure all XDR TB cases after six months of treatment. Subsequently, analysis indicated that injectable aminoglycosides were not contributing much to recovery but at least 18 drugs had activity against resistant MTBC.
Many attempts have been made to shorten the six months of treatment which is standard for all DS TB cases. A study indicated that is Rifampicin was changed with Rifapentine and Ethambutol changed with Moxifloxacin, a four month treatment was not inferior to the standard six months treatment. Recently, it has been reported that eight weeks of five drugs, Bedaquiline, Linezolid, INH, Pyrazinamide and Ethambutol was as effective as 24 months treatment, leading to better compliance.
It has also emerged that assuming Rifampicin as a surrogate marker for MDR TB was not based on facts and that INH Monoresistance (IMR) also occurs and in fact if Gene Xpert indicates Rif susceptibility but if there in IMR, for four months during the continuation phase, we would be giving only rifampicin monotherapy to these patients and would then encourage development of MDR TB.
WHO recommends adding Fluoroquinolone to IMR cases and using both Gene Xpert followed by Line Probe Assay, this two test strategy usually leads to unacceptable delay in initiating the correct evidence based regimen. With the availability of next generation molecular tests like BD Max which detects not only MTBC but also reports on both INH and Rif susceptibility, rapid evidence based management of DS TB should now be possible, without any loss of time.
With as many as 18 drugs available to chose from for treatment of MDR TB cases, WHO has classified them into three classes. Class A consists of the most active and includes moxifloxacin and Levofloxacin besides Bedaquiline and Linezolid. Class B includes Cycloserine and Clofazimine, while all others are included in class c. Ideally, a MDR TB cases should be treated with at least four drugs to which the MTBC is sensitive.
As resistance in MTBC is caused by mutation in the target gene and there are 18 drugs from which four need to be selected based on its susceptibility, performing phenotypic MIC in both difficult and costly. The development and availability of targeted Next Generation Sequencing has made it possible to simultaneously investigate all 32 genes which are targets of these 18 drugs and to report on all of them so that the individualized treatment for each patient could be based on evidence, leading to better compliance and response.
Besides treatment of active cases, persons with TB infection in which a person harbors’ latent bacteria leading to no obvious symptoms and no transmission of illness also need to be given prophylactic treatment to prevent progression onto active disease. Risk groups who would benefit most from this TB preventive Treatment (TPT) have been identified. Mantoux skin test which gave many false positive results, has now been replaced by a new skin test called Cy TB.
This consists of two MTBC-specific recombinant antigens. Either TBI can be detected by a positive reaction to this new skin test antigen, or blood can be taken and investigated in the laboratory by an interferon-gamma release assay. Treatment must be taken for three to 9 months, and various regimens have been proposed. The best appears to be one tablet of INH and rifapentine every week for 12 weeks.
The government of India has set up a portal called Nikshey in which anyone diagnosing or treating TB cases needs to feed all information. Once the information is uploaded, the patient will get nutritional support funds for the duration of the treatment. The reporting doctor would receive the incentive for both initial knowledge of the case and subsequently after treatment.
It is clear that if we hope to eradicate this ancient disease, many people will have to do a number of recommended activities actively. Together it is possible to Prevent TB to End TB.