Tuberculosis – Factors, Treatment and Diagnosis
AUTHOR : NEHA SHARMA
Tuberculosis has afflicted humanity for thousands of years all over the world. Every year on March 24, World Tuberculosis Day commemorates Dr. Robert Koch’s announcement that Mycobacterium tuberculosis was the cause of tuberculosis on March 24, 1882. Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is still a major public health concern around the world. In 2019, an estimated 10 million individuals were afflicted with tuberculosis (TB), with 1.4 million deaths recorded worldwide. India, Indonesia, China, Nigeria, Pakistan, and South Africa have the greatest TB burdens, correspondingly. These six countries account for almost 87 % of worldwide tuberculosis incidence. Active tuberculosis and subclinical or latent tuberculosis are two different types of tuberculosis. India, Indonesia, China, Nigeria, Pakistan, and South Africa have the greatest TB burdens, correspondingly. These six countries account for almost 60% of worldwide tuberculosis incidence. Active tuberculosis and subclinical or latent tuberculosis are two different types of tuberculosis. Fever, chest pains, night sweats, anemia, and weight loss are common TB clinical signs in patients with active infection .
Risk Factor of Tuberculosis
- Close contact of person with infectious Disease
- Person who immigrated from Area of the world with high TB rates
- Group with high rates of TB transmission such as homeless persons , injection drugs users and person with HIV infection
- Person with medical condition that weaken immune system
Microbiology of Mycobacterium Tuberculosis
Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium microti, and Mycobacterium canetti comprise the M tuberculosis complex of organisms, which can cause human disease. Prior to the introduction of milk pasteurisation, Mycobacterium bovis was responsible for approximately 6% of all human tuberculosis deaths in Europe. M tuberculosis is an obligate intracellular pathogen that can infect a variety of animals, but humans are the primary hosts. It is a bacillus that is aerobic, acid-fast, non-motile, nonencapsulated, and does not form spores. In tissues of high oxygen content, such as lungs, it grows most successfully. The lipid-rich cell wall is relatively impermeable to basic dyes unless combined with phenol in comparison to the cell walls of other bacteria. So, M tuberculosis is no gram positive or gram negative, but rather described as acid-fast as it resists discoloration when stained with acidified organic solvents. Non-tuberculous mycobacteria, which contain mycolic acids, are also acid-fast and cannot be distinguished from M tuberculosis on microscopic sputum smear examination. When compared to other bacteria, M tuberculosis divides every 15–20 hours, which is extremely slow. Because of the slow replication rate and ability to persist in a latent state, tuberculosis drug therapy and preventive therapy in people with M tuberculosis infection must be given for long periods of time.
Pathogenesis of Mycobacterium Tuberculosis
Four events are well defined in the pathogenesis of pulmonary tuberculosis, according to experimental models
1. Inhalation of the Mtb
Following Mtb inhalation, alveolar macrophages engulf the bacilli, which are then killed by various macrophage bactericidal mechanisms, including the production of reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI). The efficacy of these mechanisms is determined by the alveolar macrophages’ intrinsic microbicidal capacity, the pathogenic characteristics of the inhaled Mtb strain, and the inflammatory microenvironment at the infection site.
2. Inflammatory Cell Recruitment
Bacilli which survive logarithmically within alveoli and DCs, and which induce immune mediators such as TNF-α, IL-6, IL-1α and IL-1β to induce early bacterial killing to produce macrophages. IFN-is a proinflammatory cytokine produced by CD4+ and CD8+ T cells, as well as activated NK cells, in response to the production of IL-12 and IL-18 by alveolar macrophages and DCs. Peripheral inflammatory cells, such as monocytes, neutrophils, and DCs, are recruited to the lung in a local inflammatory scenario induced by Mtb proliferation. TLR signalling activates DCs, and monocytes differentiate into effector macrophages that produce microbicidal substances such as TNF-, which helps to control Mtb growth and granuloma formation.
3. Control of Mycobacteria Proliferation
This phase is marked by the inhibition of Mtb proliferation and the formation of a granuloma, as well as an efficient cell-cell interaction. Macrophages differentiate into epithelioid cells and fused giant cells as a result of chronic cytokine stimulation . The granuloma’s architecture is defined by the aggregation of T cells and infected macrophages that contain the Mtb and prevent its spread. In addition to proinflammatory cytokines (e.g., IFN-, TNF-, IL-6, IL-12, IL17, and IL23) playing a key role in the formation and stability of the granuloma, chemokines play a key role in the recruitment of inflammatory cells to form granulomas. These mechanisms allow for the development of a localised primary tuberculosis infection, which can then progress to a stable (also known as latent) infection. The central caseous infectious foci containing live Mtb is delimited by the granuloma walls in over 90% of latent infections. Mtb replication and spread are thwarted by an active cycle of cellular activation and suppression.
4. Post-Primary Tuberculosis
Latent disease may be reactivated as a result of mycobacteria persistence, which is associated with a failure in the immune surveillance system, causing damage to nearby bronchi and preparing the Mtb to spread to other areas of the lung
Clinical Symptoms of TB
- chronic cough
- night sweat
- blood- tinged sputum
- weight loss
- shortness of breath
- fever
- chest pain
- pleurisy (inflammation of the pleura membrane surrounding the lungs
DIAGNOSIS
The diagnosis of tuberculosis is based on a combination of clinical symptoms and patient history, as well as radiographic examination and bacterial detection in sputum. The presence of acid-fast bacilli (AFB) in sputum smears by microscopy does not necessarily indicate infection with Mycobacterium tuberculosis; confirmation of infection with M. tuberculosis requires microbiological culture and nucleic acid amplification-based tests. The World Health Organization recommends Xpert MTB/RIF, a cartridge-based near-patient diagnostic assay that uses real-time nucleic acid amplification of M. tuberculosis DNA to detect drug resistance to the first-line drug, rifampicin. The QuantiFERON®-TB Gold In-Tube and T SPOT.TB diagnostic assays are based on interferon gamma (IFN-) release assays (IGRAs), which take advantage of the specificity of the immune response to M. tuberculosis. Antigenspecific T-cells in the blood that recognise M. tuberculosis antigens produce IFN, which is measured by IGRAs (ESAT-6, CFP-10, TB7.7)
Traditional Mantoux skin tests rely on delayed type hypersensitivity reactions to purified protein derivatives (PPD), which are not specific to M. tuberculosis infection and can result in positive results from BCG vaccination or exposure to environmental mycobacteria. While sputum-based smear and culture techniques for clinical indication of M. tuberculosis infection are widely used, collecting sputum, particularly from children, can be difficult and unreliable. As a result, there is interest in developing TB diagnostic methods that are not based on sputum. The detection of urinary lipoarabinomannan in suspected tuberculosis cases is being investigated in HIV-positive and HIV-negative people.
Blood-based biomarkers that distinguish between LTBI and ATB are being researched for use in TB diagnostics and treatment response. The expression of HLA-DR, CD38, and Ki67 on M. tuberculosis-specific CD4 T-cells from peripheral blood has been reported to be a highly specific and sensitive method for distinguishing LTBI and ATB and evaluating treatment response. According to a recent study, HLA-DR could be a good way to tell the difference between LTBI and ATB in HIV-positive people. Understanding the range of antigen-specific responses to M. tuberculosis infection will aid in the development of diagnostics that can track infection and treatment response .
TREATMENT
A six-month regimen of four first-line drugs is currently recommended for drug-susceptible tuberculosis treatment. Rifampicin-resistant and multidrug-resistant TB treatment takes longer and costs more money. Until early 2016, WHO-recommended treatment regimens typically lasted 20 months and cost between US$ 2000 and US$ 5000 per person. For patients with pulmonary rifampicin-resistant TB (other than pregnant women), shorter 9- 12 month regimens are now recommended. According to the most recent clinical trial data, cure rates of 80% are possible, but programmatic data generally show much worse outcomes due to high rates of loss to follow-up and unevaluated treatment outcomes .
VACCINE
The only currently approved vaccination against pulmonary and extrapulmonary tuberculosis is the live attenuated BCG vaccine. It was derived from the pathogenic Mycobacterium bovis, which is primarily responsible for tuberculosis in cattle . Two French scientists, Calmette and Guerin, cultivated M. bovis in vitro for 13 years (1908–1921) and 231 passages in order to reduce its pathogenicity. The resulting bacterium, BCG, did not cause TB lesions in several animal models, but it was immunogenic and protected the inoculated animals from M. bovis attacks BCG is the only licenced vaccine for human tuberculosis prevention. It is a live, attenuated vaccine obtained by continuous subculture of Mycobacterium bovis . The Institute Pasteur in France was the first to distribute the BCG vaccine strain. Over the years, different passages and culture methods have resulted in the development of more than 14 BCG strains with various phenotypes and genotypes all over the world. Currently, four major strains, BCG Pasteur 1173P2, BCG Danish 1331, BCG Glaxo 1077, and BCG Japan 172, account for more than 90% of BCG used worldwide .
Problems with BCG
It is a low-cost, widely available vaccine that is given to more than 90% of children in countries where the disease is prevalent. However, the same vaccine cannot protect against adult pulmonary tuberculosis on a homogeneous basis among the world’s population, with highly variable protection ranging from 0 percent to 80 percent. The effects of this vaccine on the prevention of childbirth and meningeal or military tuberculosis have been very positive . The WHO considers developing and implementing new TB vaccines to be a top priority. As a result, in 2017, the organisation proposed a “WHO preferred product characteristics” guideline for the development of these vaccines, which was presented to experts from various branches of the industry, including scientists, funding agencies, and regulators. Given the disease’s complexity, and in order to effectively target the various states of infection, latent or active, TB vaccination should provide several layers of protection, namely by preventing initial infection, reactivation of infection, or progression into active disease. Furthermore, the vaccine should be suitable and safe for use in immune-compromised patients, such as HIV positive individuals. While the WHO also mentions the need for research on a new infant tuberculosis vaccine.
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