Tuberculosis: Etiology and Patho-physiology, Classification, Clinical Manifestations and Complications

December 3, 2019

An infectious disease which is caused by Mycobacterium tuberculosis is called tuberculosis.
It is a primary cause of death worldwide that is a potentially curable infectious disease.
Death of HIV patients is mostly due to the secondary infection i.e. tuberculosis.
The incidence of TB worldwide was decreased until the mid-1980s when HIV disease emerged.
There are various factors responsible for resurgence of TB. The major of them are: 1) high rates of TB among patients with HIV infection and 2) the emergence of MDR strains of M. tuberculosis.
Worldwide about 2 billion people are currently infected with TB which is one third of the total population.
Each year, 1.8 million people develop TB and 0.8 million are new smear positive highly infectious cases.
The average annual risk of infection is estimated to be about 1.5% and 5000 people develop it every-day.
This disease occurs more in poor and under-served people as compared to others.
Homeless, residents of inner city neighborhoods, slums, those living or working in institutions (long-term care facilities, prisons, shelters, hospitals), IV injecting drug users, people at poverty level and those with poor access to health care are at high risk.

Immune-suppression from any diseases like HIV infection, malignancy, long-term corticosteroid use also put the people to high risk of active TB infection.
Once a strain of M. tuberculosis develops resistance to two of the most potent first-line anti-tuberculosis drugs like isoniazid (INH)and rifampin, the TB is called MDR-TB i.e., multi-drug resistant TB.
If the bacteria resist any one of the fluoro-quinolones plus any injectable antibiotic agent then it is known as extensively drug-resistant TB (XDR-TB).
There are several problems that increase the resistance of bacteria towards drugs like incorrect prescribing, lack of public health case management and patient non-adherence to the prescribed regimen.

Etiology and Patho-physiology

It is a gram positive, acid-fast bacillus (AFB) that usually spreads from one person to another through droplet infection which is produced when one speaks, talks, sneezes, coughs.
Small droplet nuclei are formed in a process of evaporation which is 1-5 micron in size that remains suspended in the air from minutes to hours.
These nuclei get transmitted to healthy person during inhalation.
TB is not highly infectious as it requires close, frequent or prolonged exposure.
Brief exposure to a few tubercle bacilli may not result to the infection.
Touching, sharing food utensils, kissing or any other type of physical contact may not transfer disease to others.
Transmission may be influenced by various factors like 1) number of organisms that have been expelled into the air, 2) concentration of organisms (small spaces with limited ventilation would mean higher concentration), 3) exposure time and 4) immune system of the exposed person.
Once the droplet nuclei are inhaled, they lodge the bronchioles and alveolus where a local inflammatory reaction occurs and the focus of infection is established.
This is called the Ghon Focus which later on develops to granuloma, the hall mark of TB.
Granuloma formation is a defense mechanism aimed at walling of the infection and preventing further spread.

Bacillus replication is thus inhibited and the infection is stopped.
70% of the immune-competent adults can completely kill the mycobacteria while the rest of them contain the mycobacteria in non-replicating dormant state.
Of these individuals, 5-10% develops active TB infection as soon as the bacteria begin to multiply after months or years later.
The infection can spread via the lymphatic system and the growth of bacteria occurs in other organs like kidneys, epiphyses of the bone, cerebral cortex and adrenal gland after finding favorable environment.

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Classification of Tuberculosis

TB can be classified using several systems.
According to the American Thoracic Society, TB is classified on the basis of its development.
TB can also be classified according to its 1) presentation (primary, latent or reactivated) and 2) whether it is pulmonary or extra-pulmonary.

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Primary infection occurs after the inflammatory reaction is initiated on inhalation of bacteria.
The majority of people mount effective immune responses to encapsulate these organisms rest of their lives which prevents primary infection to progress further to disease.
Latent TB infection (LTBI) occurs in a person who lacks active TB disease.
These individuals are asymptomatic and are unable to transmit the TB bacteria to others.
An estimated 10-15 million Americans have LTBI among which 5-10% will develop active TB at some point in their life so LTBI treatment is important.
Active TB disease results after the replication of bacteria that is possible only if the initial immune response is not adequate and the body cannot contain the organisms.
The TB is called primary TB if active TB develops within the first two years of infection.
The TB disease occurring 2 or more years after the initial infection is called post-primary or reactivation TB.
HIV infected individuals are at greater risk of developing active TB.
Reactivation of LTBI precipitates in immune-suppression, diabetes mellitus, poor nutrition, aging, pregnancy, stress and chronic disease.
The individual is considered to be infectious and is able to transmit the disease if the site of TB is pulmonary or laryngeal.

Clinical Manifestations

People who have LTBI show positive skin test but they are asymptomatic.
Symptoms of pulmonary TB do not develop until 2 to 3 weeks following infection or reactivation.
An initial dry cough that frequently becomes productive with mucoid or muco-purulent sputum is the manifestation for pulmonary TB.

Some constitutional symptoms such as fatigue, malaise, anorexia, unexplained weight loss, low-grade fevers, and night sweats are also noticed.
Dyspnea is noticed as a late symptom that may signify considerable pulmonary disease or pleural effusion.
Hemoptysis also occurs in 10% cases that appear as late symptom.
In some cases, TB has more acute sudden presentation such as the patient may have a high fever, chills, generalized flu-like symptoms, pleuritic pain, and a productive cough.
Auscultation of lungs may be normal or reveal crackles, rhonchi, and/or bronchial breath sounds.
Patients those who are immune-suppressed and older adults may not have fever and other signs of infection.
HIV patient may have classic manifestation of TB such as fever, cough and weight loss which may be wrongly attributed to PCP or other HIV associated opportunistic diseases.
Respiratory problems in case of HIV patients must be carefully investigated to determine the cause.
If there is change in cognitive function, then only it can be initial presenting sign of TB in an older person.
The clinical manifestations of extra-pulmonary TB depend on the organs infected.
For example: in case of renal TB there may be signs like dysuria, and hematuria. Bone and joint TB may show sign like severe pain. Headaches, vomiting and lymphadenopathy may be the symptoms in TB meningitis.

Complications

If pulmonary TB is appropriately treated then there may be no any complications after healing process except for a scar and residual cavitation within the lungs.
Significant pulmonary damage that is rare can also occur in patients who care poorly treated or who do not respond to anti-TB treatment.
Miliary TB is the wide-spread dissemination of mycobacterium.
The bacteria are spread through the bloodstream to distant organs which may be characterized by a large amount of TB bacilli and may be fatal if left untreated.
It may occur as a result of primary disease reactivation of latent infection.
The miliary TB clinical manifestations slowly progress after a period of days, weeks or even months.
Symptoms may differ depending on the organs infected.
Hepatomegaly, splenomegaly and generalized lymphadenopathy may be present.
Pleural TB may occur from either primary diseases reactivation of a latent infection.
Pleural effusion is caused in the pleural space by the bacteria which trigger an inflammatory reaction and a pleural exudate of protein-rich fluid.
If there is large numbers of tubercular organisms in the pleural space, empyema may occur though it is less common than effusion,
If large numbers of tubercle bacilli are released from granulomas into the lungs or lymph nodes, it may result to acute pneumonia.
The clinical manifestations resemble to the bacterial pneumonia.
Various acute and long term complications may result as TB can infect organs throughout the body.
Spinal TB (Pott’s disease) can lead to destruction of the inter-vertebral disc and adjacent vertebrae.
Central Nervous System TB can cause severe bacterial meningitis whereas abdominal TB can lead to peritonitis especially in HIV-positive patient.
The kidneys, adrenal glands, lymph nodes and urogenital tract can also be affected by TB.