Active Tuberculosis

Article Author:
Talha Jilani
Article Editor:
Abdul Siddiqui
Updated:
9/8/2018 8:12:13 AM
PubMed Link:
Active Tuberculosis

Introduction

Active tuberculosis is a condition in which the body’s immune system is unable to fight off or defend against the Mycobacterium tuberculosis bacterium. This inability causes an infection of the lungs, which is the most common presentation, or other parts of the body (tuberculosis is a multisystemic disease). Apart from the respiratory system, the organ systems most commonly affected include the gastrointestinal system, the musculoskeletal system, the lymphoreticular system, and the reproductive system, as well as the skin and the liver.

Most individuals infected with tuberculosis do not show symptoms, which is known as latent tuberculosis. However, around 5% to 10% of patients with latent infections progress to active disease, which is a serious concern. If untreated, half of those with the active disease die.

The World Health Organization estimates that, annually, around 8 million people develop active tuberculosis globally and nearly 2 million people die from the disease. Of every 10 people infected with M. tuberculosis, one may develop an active infection sometime in their lifetime. After infection, the risk of developing active tuberculosis is highest in the first year, but the active disease usually occurs many years later in most patients.

The World Health Organization (WHO) reported in 2017 that the estimated global incidence rate for tuberculosis has decreased by 1.5% each year since 2000. However, despite these substantial gains and drastic global efforts to eradicate tuberculosis, the disease still accounts for significant morbidity and mortality worldwide. Developing countries like India, Pakistan, the Philippines, China, South Africa, Indonesia, and Nigeria experience the highest morbidity and mortality rates. When combined, these countries accounted for 64% of all tuberculosis-related deaths in 2016, according to the WHO.

Etiology

Infection with Mycobacterium tuberculosis (alcohol and acid-fast bacillus) causes active tuberculosis. It is classified under the M. tuberculosis complex group, which includes 4 other mycobacteria that can cause active tuberculosis: M. canettii, M. microti, M. bovis, and M. africanum.

M. tuberculosis is an obligate-aerobic (needs oxygen to survive), nonmotile (no flagellum), non-spore-forming, catalase-negative, facultative (can make ATP by aerobic and anaerobic processes), intracellular bacteria. The high lipid content of M. tuberculosis gives it many unique clinical characteristics. These include resistance to several antibiotics and ability to survive in many extreme conditions. It also takes a long time to divide (around 16 to 20 hours), a significantly slower rate compared to other bacteria, which usually take less than an hour.

The organism has a poor reaction to Gram stain and thus is not classified as gram-positive or gram-negative. However, sometimes weakly positive cells are observed on Gram stain, referred to as “ghost cells.” As M. tuberculosis retains some stains even after being treated with solutions containing acids, it is considered an acid-fast bacillus. The Ziehl-Neelsen stain and the Kinyoun stain are most commonly used to identify M. tuberculosis. The tests dye the acid-fast bacilli bright red which makes it distinct against a blue background.

Humans are the only known population in which M. tuberculosis naturally lives and reproduces. The organism is spread primarily as an airborne aerosol from an individual in the infectious stage of tuberculosis, although transdermal and gastrointestinal (GI) transmission is also possible.

Epidemiology

Tuberculosis has a global distribution, and over two billion people (around 30% of the world's population) are suspected to be infected with M. tuberculosis. In 2003, the global incidence of tuberculosis reached its peak but has been declining slowly ever since. Most new cases of the disease in 2016 were reported from Asia (around 45%), followed by Africa (around 25%). The WHO reported in 2016 that approximately 10.4 million people became infected with tuberculosis, of which approximately 1.7 million died.

Although present globally, the epidemiology of tuberculosis varies significantly depending on the region.

  • India, sub-Saharan Africa, Micronesia, and the islands of Southeast Asia had the highest rates (100 per 100,000 people or higher)
  • China, Eastern Europe, Central and South America, and northern Africa had intermediate rates (26 to 100 cases per 100,000 people)
  • The United States, Canada, Japan, Western Europe, and Australia recorded the lowest rates (less than 25 cases per 100,000 people)

Although about 90% to 95% of the people infected with M. Tuberculosis do not develop active disease and remain asymptomatic, around 5% to 10% of those infected develop the disease. In 2012, this amounted to around 8.6 million cases of active tuberculosis worldwide.

Young adults have the highest rates of active tuberculosis globally, but in developed countries, older individuals experience the highest rates of disease. People of all age groups are at risk of progressing to active disease. Those at increased risk include:

  • Patients also infected with HIV are 20 to 30 times more likely to develop active tuberculosis.
  • People with other conditions that suppress the immune system are also at a higher risk of progressing to active disease. This group includes people on immunosuppressive agents such as long-term corticosteroids.
  • People with chronic lung diseases.
  • The use of tobacco products also increases the risk of progressing to active disease and death.
  • Malnutrition indicates a higher risk of progressing to active disease, making tuberculosis one of the principal illnesses of poverty.
  • Patients who have diabetes also have an increased risk of progressing to active tuberculosis and experience worse treatment outcomes.
  • The use of alcohol (greater than 40 g per day) also increases risk.

Pathophysiology

Inhaling the aerosolized droplets from an infected person is the principal mechanism through which tuberculosis spreads. Although tuberculosis most commonly causes a lung infection, it is a multisystemic disease which is a great mimic and can present as variable pathologic findings. Subsequent deposition of the organism in the lungs can lead to a few possible outcomes, including:

  • The immediate clearance of the organism from the body
  • Primary disease: The immediate onset of active disease in the individual
  • Latent infection
  • Reactivation disease: The onset of active disease many years after a period of latent infection

The body’s ability to effectively restrict or eliminate the infective inoculum is dependent on the immune status of the individual, genetics, and whether exposure to the organism is primary or secondary. M. tuberculosis also possesses several virulence factors that make its elimination difficult for alveolar macrophages. These factors include the high mycolic acid content found in the bacterium’s outer capsule, which makes phagocytosis difficult for alveolar macrophages. Other constituents of the bacterium’s cell wall such as the cord factor could directly damage the alveolar macrophages. Several studies have demonstrated that M. tuberculosis also inhibits the formation of an effective phagolysosome, which limits and sometimes even prevents the elimination of the organisms. Other virulence factors include catalase-peroxidase, which helps resist the oxidative response of the host cell, and lipoarabinomannan, which helps induce cytokines and resist host oxidative stress.

Individuals who fail to eliminate the mycobacterium after the first contact develop primary tuberculosis. The primary disease develops in approximately 5% to 10% of exposed individuals, and of these, roughly half develop active tuberculosis within the first 2 to 3 years after infection.

The tubercle bacilli induce infection of the lungs after they are transported in droplets small enough to reach the alveolar space (around 5 to 10 microns). If the infection is not eliminated by the innate defense system of the host, the bacilli could proliferate inside alveolar macrophages, which could migrate away from the lungs and enter other tissues.

Macrophages in the lungs produce chemokines and cytokines that attract other phagocytic cells, including neutrophils, monocytes, and other alveolar macrophages, which produce a nodular granulomatous structure known as a tubercle. If the continuous bacterial replication is not inhibited, the enlarging tubercle and bacilli could enter local draining lymph nodes. This causes lymphadenopathy, which is a characteristic manifestation of primary tuberculosis. A Ghon complex can develop if the lesion produced by the extension of the tubercle spreads into the lung parenchyma and lymph node. Bacteremia could also be seen in initial infection.

The tubercle bacilli will proliferate until an effective cell-mediated immune response develops. This usually takes about 2 to 10 weeks following initial infection in more than 90% of infected individuals. In the lungs, failure to mount an effective cell-mediated immune response and tissue repair could lead to extensive damage. Tumor necrosis factor-alpha, nitrogen intermediates, reactive oxygen, and the constituents of cytotoxic cells (perforin, granzymes) whose function it is to eliminate M. tuberculosis could also contribute to collateral damage of the host and the development of caseating necrosis. Therefore, much of the tuberculosis pathology results from the infected host's immune response to the tubercle bacilli.

Unchecked bacterial growth could lead to the hematogenous spread of bacilli and eventually disseminated tuberculosis. "Military tuberculosis" is the term for disseminated disease with lesions resembling millet seeds. The bacilli can also spread mechanically via erosion of the caseating lesions into the airways, at which time the host becomes infectious to other individuals. In the absence of treatment, the mortality rate is around 80%. The remaining patients could develop a chronic disease or recover. Chronic tuberculosis is characterized by recurrent episodes of healing by fibrotic changes surrounding the lesions and tissue breakdown. The complete spontaneous eradication of the tubercle bacilli is rare.

The primary tuberculosis infection is usually located in the middle portion of the lungs and is referred to as the Ghon focus. The Ghon focus usually enters a state of latency in most individuals, known as latent tuberculosis. If there is immunosuppression in the host, latent tuberculosis is capable of being reactivated.

Most individuals who develop tuberculosis do so after an extended latency period, often many years after the initial primary infection. This is known as reactivation disease or secondary tuberculosis. Individuals with latent infection but no underlying medical problems have a 5% to 10% risk of developing secondary tuberculosis in their lifetime. The location of the lesions of secondary tuberculosis is usually at the lung apices, and unlike primary disease, tends to be localized. A small number of people could also develop secondary tuberculosis after getting reinfected with M. tuberculosis. Secondary tuberculosis can be differentiated from primary progressive tuberculosis by the presence of cavitation and the location of the lesion.

Histopathology

The diagnostic histopathological hallmark of tuberculosis is a granuloma. The differentiating features of a tuberculosis granuloma include the presence of multinucleated giant cells and caseous necrosis demonstrable through a region of central eosinophilia.

History and Physical

The classic symptoms of active pulmonary tuberculosis include a chronic cough associated with hemoptysis, weight loss, and night sweats. Many patients also experience fever, chest pains, and weakness. 

When taking the history of a patient with the above symptoms, a physician should also inquire in detail about the following factors, as they increase the likelihood that the patient could have an active tuberculosis infection:

  • History of HIV infection
  • History of prior tuberculosis treatment
  • History of a positive purified protein derivative of tuberculin test result
  • Emigration from or travel to an area where tuberculosis is endemic

The presentation of secondary tuberculosis is different from that of primary progressive disease as the hypersensitivity and tissue reaction are more severe in secondary tuberculosis, and cavities are usually observed in the upper portion of the lungs.

Active disease could also result in pulmonary or systemic dissemination of tubercles, and this could manifest as miliary tuberculosis, which resembles millet-shaped lesions on radiographic images of the chest. Tuberculosis could also spread into the bowel, spine (Pott disease), or central nervous system (tubercular meningitis).

Evaluation

Screening Tests    

The Mantoux Test

The Mantoux test consists of injecting the individual with a dose of purified protein derivative and observing the skin for induration. This method is the traditional screening test for exposure to tuberculosis. The patient’s overall risk of exposure is taken into consideration when interpreting the result. Patients are then classified into three groups based on the size of induration and the risk of exposure. These 3 groups include:  

  • Low risk: These patients have a minimal probability of exposure to tuberculosis. The Mantoux test is only considered positive if there is significant induration of 15 mm or higher following the intradermal injection of purified protein derivative. People in this group include those with no history of travel to a tuberculosis-endemic region, no history of military service, no contact with a patient with a chronic cough, no history of steroid use, no known occupational exposure, are negative for HIV, and are not a resident of a tuberculosis-endemic country.
  • Intermediate risk: These patients have an intermediate probability of exposure to tuberculosis. Their test results are considered positive if the measured induration is greater than 10 mm. People in this group include those who are residents of tuberculosis-endemic countries such as Asia, Latin America, and Africa, residents or workers of shelters, those who reside in overcrowded vicinities, and medical personnel.
  • High risk: These patients have a significant probability of exposure to tuberculosis. Their test results are considered positive if the measured induration is greater than 5 mm. People in this group include those who are immunocompromised and cannot mount a sufficient immune response to the purified protein derivative test (HIV-positive patients, those on chronic steroids), patients with frequent exposure to those with persistent cough, and patients with evidence of a prior tuberculosis infection, such as a healed scar seen on X-ray.

A positive Mantoux test indicates exposure to tuberculosis or latent tuberculosis. However, this test lacks specificity, and patients require subsequent visits to interpret the result and a chest x-ray for confirmation of the disease. Although the test is considered relatively sensitive, it may give false positive results if the patient has been administered the BCG vaccine. The Mantoux test should never be regarded as a confirmatory test.

Interferon Release Assays

This is a far more specific screening test that is just as sensitive as the Mantoux test. It qualitatively assesses the level of inflammatory cytokines such as interferon gamma. The advantage of this test, especially in those inoculated with the BCG vaccine, is that the test requires only a single blood draw, which negates the need for repeat visits by the patient to interpret results. Furthermore, additional investigations such as HIV screening could be performed on the same drawn sample of blood, after consent. Some disadvantages of this method include its high cost and need for technical expertise to perform the test.

Additional Information on Screening Tests

A positive result on a screening test indicates that the individual has had exposure to tuberculosis and has a high chance of developing active disease in the future. The incidence of tuberculosis in those patients who had a positive Mantoux test is around 2% to 10% without treatment.

Patients who have a positive screening test should have at least a basic diagnostic test like a chest X-ray performed. In certain cases, the patients should have additional tests. Patients with a negative diagnostic test result who do not meet the criteria for active disease should receive prophylaxis with isoniazid for latent disease if they meet the criteria.

Patients who are immunocompromised may show lower levels of induration to the purified protein derivative or a false-negative Mantoux because of cutaneous anergy.

When reviewing negative screening results for tuberculosis in HIV-positive patients, a high level of suspicion should be entertained. 

Confirmatory Tests

These tests are performed after positive screening tests, or after negative screening tests in patients with high suspicion of disease, to confirm active disease. Confirmatory tests include:

  • Chest x-ray, which can determine the presence of active disease in all positive screening tests
  • Culture
  • Acid-fast staining, or Ziehl-Neelsen stain
  • Nuclear amplification and gene-based tests

Nuclear amplification and gene-based tests represent a new generation of tools used for the diagnosis of tuberculosis. These tests enable the identification of the bacteria or bacteria particles by making use of DNA-based molecular techniques. These techniques are faster and allow accelerated diagnosis with high precision. Confirmation of the tuberculosis infection could be made in a few hours compared to the days or weeks it usually takes to wait for a standard culture. These tests are especially important among immunocompromised patients for whom there is a high rate of false negative results. A few of the molecular-based tests such as DR-MTB and GeneXpert also allow for identification of multiple-drug-resistant tuberculosis infections.

Treatment / Management

Patients with a possible tuberculosis infection should be isolated in a private room with negative pressure, either through a high-efficiency particulate air filter or by exhausting the air outside. The medical staff should always wear high-efficiency disposable masks to filter the tubercle bacillus. Isolation should continue until collected sputum smears are negative for three consecutive determinations, usually after approximately 2 to 4 weeks of treatment. Unfortunately, these measures are neither practical nor possible in developing countries where tuberculosis is a public health problem.

Treatment of an active tuberculosis infection requires a combination of drugs. Monotherapy should never be used for the active disease to reduce the risk of the mycobacterium developing antibiotic resistance. First-line medications are the most commonly used regimens for active tuberculosis, including:    

  • Isoniazid: This is given with vitamin B6 to prevent neuropathies.
  • Rifamycin: Patients should have baseline and follow-up liver function tests done as rifamycin is hepatotoxic.
  • Ethambutol: Used only in children whose visual acuity can be determined and monitored (usually older than 6 years), as ethambutol can cause optic neuritis.
  • Pyrazinamide: Patients should have periodic liver function tests, chest X-rays, serum uric acids, and sputum cultures done at 2 to 3 months and at the completion of treatment.

The four-medication combination (isoniazid, rifampin, ethambutol, and pyrazinamide) is administered for 2 months, followed by a combination of isoniazid and rifampin for 4 months.

Directly observed therapy is recommended for patients receiving treatment. With this type of therapy, patients on the above regimens could be switched to 2 to 3 times per week dosing after completing an initial 2 weeks of daily dosing. Those taking medication 2 times per week must not miss any doses. Daily therapy should be prescribed for patients who are on self-administered medication. 

Patients diagnosed with active tuberculosis should have sputum analysis done for M. tuberculosis every week until sputum conversion is documented.

Second-line medications include: 

  • Injectable Aminoglycoside: Streptomycin, amikacin, and kanamycin.
  • Injectable polypeptides: Viomycin and capreomycin
  • Fluoroquinolones: Levofloxacin, gatifloxacin, ofloxacin, and moxifloxacin
  • Others: Para-aminosalicylic acid, ethionamide, cycloserine, prothionamide, terizidone, linezolid, and thioacetazone.

Third-line anti-tuberculosis medications are drugs with variable but unproven efficacy against the disease. They are the last resort for total drug-resistant tuberculosis infections and include:

  • Amoxicillin/clavulanic acid
  • Clarithromycin
  • Clofazimine
  • Linezolid
  • Imipenem/cilastatin

Multiple-drug-resistant tuberculosis infections are becoming increasingly common. A high-dose combination of the first-line and second-line drugs is being used to treat this condition. 

Prognosis

The mortality rate for those with an active tuberculosis infection who do not receive adequate treatment is around 50%. Those at an increased risk for worse outcomes and possible death include:

  • Young children (especially infants) and elderly patients
  • Those who have a delay or do not receive proper treatment
  • Patients who display an extensive spread of the disease on radiologic imaging
  • Patients who have a severe respiratory compromise
  • Those who are taking drugs or suffer from a disease that causes immunosuppression

Complications

Complications from active tuberculosis are frequently seen in patients with the risk factors mentioned above. Patients who do not receive proper or complete treatment for active disease are also at a higher risk of developing complications. Some complications caused by active disease include:

  • Acute respiratory distress syndrome
  • Extensive destruction of the lung
  • Empyema
  • Pneumothorax
  • Disseminated tuberculosis infection (including tubercular meningitis)