Tuberculosis as an Old Disease with New Perspectives

Tuberculosis is one of the most common communicable diseases worldwide. It increases in poor socioeconomic conditions and in cases of immune suppression. The widespread HIV and immune suppressive diseases, as well as the high prevalence of many autoimmune disorders which are mainly treated with immune suppressive drugs, led to increasing in the overall new cases of tuberculosis. Many methods are used in the diagnosis of tuberculosis such as smear, culture, X-ray, and others, but the most rapid and sensitive is the detection of tubercle bacilli nucleic acid. Multiple drugs are used in combination to treat active tuberculosis like isoniazid and rifampicin, but the multi-drug resistance and the long duration of drug therapy encouraged the researchers the discovery of new drugs. Prevention of tuberculosis includes many procedures, for example, proper treatment of cases and improvement of socioeconomic standards together with BCG vaccination. Some countries give BCG vaccination as a compulsory vaccine for children in the first months of life, while other countries give it to exposed individuals only. Recently, some researchers claim that countries giving BCG vaccination early in life may have a reduced incidence of Covid-19, but plenty of other studies are still needed to confirm or deny this.

Introduction

Tuberculosis remains one of the leading causes of death from infectious diseases among adults worldwide, with more than 10 million people becoming newly sick from tuberculosis each year. It is a contagious infectious disease caused mainly by Mycobacterium tuberculosis (pulmonary type) or Mycobacterium bovis (intestinal type). It affects mainly the lungs, but can also affect other parts of the body. The pulmonary type is an airborne disease, that spreads mainly when an infected person coughs, sneezes, or spits saliva droplets containing tubercle bacilli that are to be inhaled by an uninfected close person. The intestinal type is caused mainly by the ingestion of milk contaminated with Mycobacterium bovis.

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The tubercle bacilli find their way into the human body through the respiratory tract and due to their minute small size can reach the lower airways. Inhalation of the Mycobacterium tuberculosis organisms may give rise to latent tuberculosis infection (LTBI), which is asymptomatic, with a 5-10% risk of developing into active tuberculosis (TB). LTBI serves as a reservoir for new diseases and the ongoing cycle of transmission within communities. The risk of reactivation and acquiring the active disease is affected by poverty, overcrowding, poor housing, and chronic debilitating diseases and individuals with HIV coinfection, therapy with TNF-α inhibitors, type 2 diabetes, and other states of relative immunosuppression (e.g., transplant patients and the elderly).

Annual rates of infection range from 4.2% in South Africa and 1.7% in Vietnam to 0.03% in the United States due to better and more advanced living conditions. The disease progresses at a higher rate among infants and very young children who have latent tuberculosis infection than in older children with latent infection. Nowadays, tuberculosis re-emerged again as one of the important diseases due to the widespread of HIV and other immunosuppressive disorders and drugs.

Pathogenesis

After exposure and inhalation of Mycobacterium tuberculosis, innate immune responses, including alveolar macrophages and granulocytes, begin to fight the infection, in some people succeed in the eradication and removal of the tubercle bacilli, however, in others infection is settled.

The infection success is dependent on four steps respectively: phagocytosis of the bacilli, their intracellular multiplication, latent contained phase of infection, and, finally, active lung infection. A membrane-bound vesicle called ‘phagosome’ stores the bacterium engulfed by the macrophage. The bacilli can proliferate inside the macrophages by inhibiting the fusion of phagosome and lysosome. Lymphatic and hematogenous dissemination are the results of the replication of the bacilli in the macrophages and the regional lymph nodes, which can lead to the development of extrapulmonary disease in any part of the body.

This process of dissemination primes the immune system for a systemic response. The host enlists the help of various immune cells to the site of infection, resulting in the formation of an aggregate of cells referred to as the granuloma, which is the classical hallmark of the disease. The activated immune cells, such as T-helper 1 (Th1) that migrate to the inflammatory focus, secrete proinflammatory cytokines like interferon-gamma and other lymphokines that stimulate the production of nitric oxide to try to limit the spread of infection and enhance macrophage-killing. The immune response despite being largely effective causes tissue destruction with the formation of caseation and necrosis inside granulomas.

Pathology

There are two pathological types, which are productive and exudative. Productive lesions are tubercles or granulomas, formed by the recruitment of inflammatory cells, and later caseation and central necrosis occur. The main cells that form the granulomas are the activated macrophages, lymphocytes, and Langhans giant cells. It occurs mainly when the bacillary load is small and the immune system dominates. Exudative lesions are tuberculous pneumonia, which is characterized by excess serous exudate, which contains a large number of neutrophils, and loose aggregates of immature macrophages with extensive and rapid caseation. It occurs mainly when a large number of bacilli are present with a weak immune system.

Tuberculosis can also be classified according to the affected site into pulmonary and extrapulmonary. The pulmonary type includes primary and secondary tuberculosis. The primary pulmonary develops in previously unexposed individuals, and the source of the organism is always exogenous, occurring mainly at a young age (childhood) and forming the primary pulmonary complex. This complex includes Gohn’s focus, pulmonary lymphangitis, and pulmonary lymphadenitis. Gohn’s focus is small focus on the inflammation that develops in the base of the upper lung lobe or the upper part of the lower lobe. The primary complex may heal by fibrosis, spread either directly into the lung and pleura or through the blood, or encapsulate and remain dormant (latent infection) that could be reactivated if the immunity is lowered. Secondary pulmonary tuberculosis affects mainly adults and occurs due to reinfection or reactivation of primary pulmonary lesions due to reduced immunity. It starts always at the apex of the lung and may heal by fibrosis or progress to fibrocaseous or acute caseous tuberculous pneumonia.

Clinical Picture

General signs and symptoms include fever, chills, night sweats, loss of appetite, and weight loss. Significant nail clubbing may also occur. In active pulmonary tuberculosis, symptoms may include chest pain and prolonged cough-producing sputum. Occasionally, people may cough up blood in small amounts, and in very rare cases, the infection may erode into the pulmonary artery, resulting in massive bleeding.

Extrapulmonary tuberculosis involves any part of the body other than the lungs. It affects about 15-20% of active cases and the clinical picture is dependent on the affected organ. Notable extrapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott’s disease of the spine), among others. A potentially more serious, widespread form of TB is called 'disseminated tuberculosis'.

Diagnosis

Active tuberculosis diagnosis is mainly dependent on the laboratory diagnosis since the clinical picture is almost non-specific. Many techniques are used to diagnose tuberculosis. Isolation of the bacilli from different specimens (sputum, stool, urine, CSF, lymph node, or any tissue biopsy) and their staining with Ziehl-Neelsen stain can detect the characteristic acid-fast bacilli. The smear staining technique is dependent on the presence of a large number of the bacilli so sometimes, culture is done on Löwenstein-Jensen (LJ) medium, but it takes from 3-4 weeks for the colonies to appear, and negative results couldn’t be concluded before 8 weeks.

Other techniques are also important, such as chest X-rays, and nucleic acid detection which is the most rapid and sensitive method. Other methods like Interferon-γ release assays (which measure the amount of IFN-γ produced in response to the ESAT-6 and CFP-10 antigens from Mycobacterium tuberculosis) are of little value in developing countries but could help in a patient with HIV.

The tuberculin Mantoux test is an intradermal test used in the screening of people who are suspected to have latent TB. It depends on the cell-mediated immune response to tuberculosis (delayed hypersensitivity reaction). It could be considered a good negative test to exclude infection, but it could be falsely negative in patients with overwhelming tuberculosis, Hodgkin’s disease, measles, or immune suppression, and could also be falsely positive in people vaccinated with the BCG vaccine.

Treatment, Prevention, and Control

For pan-susceptible tuberculosis, treatment still consists of four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) given for a total of 2 months, followed by two drugs (isoniazid and rifampicin) given for an additional 4 months. Some cases can require durations of more than 6 months to achieve a cure. Studies have shown that daily administration of therapy results in improved treatment outcomes compared with thrice-weekly treatment, and WHO recommends all people diagnosed with tuberculosis be offered daily treatment with fixed-dose combinations. Recently, two new drugs, bedaquiline and delamanid, entered the tuberculosis treatment plan, and many clinical trials are being done. They are of great importance, especially in ordinary treatment-resistant strains.

Prevention efforts for tuberculosis rely mainly on vaccination and the treatment of latent tuberculosis or active tuberculosis infection, together with the improvement of socioeconomic conditions and eradication of TB in cattle and milk pasteurization to prevent M. bovis. Immunization with the BCG vaccine is known to protect children from severe and disseminated forms of disease and decrease infection by 30%. In general, the vaccine is not thought to be immunogenic enough to induce long-term immunity, although some studies show that intrapulmonary administration might be more immunogenic, and the development of an inhaled BCG vaccine could be an important strategy to pursue. The BCG vaccine is a live attenuated M. bovis strain called (bacillus-Calmette-Guerin). In Egypt, it is given to newborns during the first month of life and to adults who are exposed to infection, such as doctors and nurses. This vaccine has also a non-specific stimulation of cell-mediated immunity, hence, some studies denoted that it possibly may give strong immunity to individuals, decreasing the incidence of Covid-19 infection and severe disease.

Conclusion

Tuberculosis is a serious ancient disease, and despite newer ways for diagnosis and treatment of TB, unfortunately, people are still suffering, and worldwide it is among the top 10 killer infectious diseases, second only to HIV. Although it can affect people of any age, individuals with weakened and suppressed immune systems, e.g., with HIV infection, elderly, or transplant patients are at increased risk. To eliminate the disease, actions like pasteurization of milk before marketing and organized goat/sheep abattoirs should be made mandatory under the law, where milk samples and carcasses can be routinely tested/examined for TB. Vaccination of our livestock against TB and routine screening of livestock (e.g., on a yearly basis at the farms and also at the animal fairs) should be made obligatory. Our fight against TB will be incomplete without considering the zoonotic aspect of this deadly disease. Moreover, improvement of socioeconomic standards together with BCG vaccination can lead to a TB-free world.

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