Extrapulmonary Tuberculosis

Tuberculosis, or TB, is an airborne infectious disease caused by Mycobacterium tuberculosis. It most commonly affects the lungs where it is called pulmonary TB. When the infection occurs in other parts of the body it is called extrapulmonary tuberculosis. Tuberculosis is the most common fatal infectious disease in the world: one-third of the world's population is currently infected and more than 1.5 million people die each year due to tuberculosis. About 15 % of TB cases are extrapulmonary. Extrapulmonary tuberculosis has become more common since the advent of human immunodeficiency virus (HIV) infection.

Other Names

 * Scrofula (when affecting lymphatic system)
 * Pott disease (when affecting the spine)
 * Miliary tuberculosis (when disseminated)

Types
TB is usually classified based on the disease symptoms and site of infection.

Extra-pulmonary tuberculosis refers to disease outside the lungs. It is sometimes confused with non-respiratory disease. Disease of the larynx for example, which is part of the respiratory system, is respiratory but extra-pulmonary. In developed countries, 10-15% of TB cases have extra-pulmonary involvement, but in patients from high-incidence countries the rate is much higher. People who are HIV positive and infected with TB develop extra-pulmonary disease much more frequently, up to 50% of cases.

Both during the initial (or primary) infection with TB and during any subsequent secondary active disease the bacteria are spread by blood or the lymphatic system to other parts of the body. In healthy people these bacteria are usually destroyed by the immune system. If some immune deficit is present some may concentrate at a particular site where they may lie dormant for years or even decades before causing disease.

The most common sites of infection for extra-pulmonary TB in order of frequency are:


 * Lymph glands
 * Pleura (membrane than covers the lungs)
 * Genito-urinary tract. In women uterine disease is probably the most common while in men the epididymis is the site most frequently affected. Both sexes are affected by renal or bladder disease equally.
 * Bones and joints (also called osteotuberculosis)
 * Meninges, which may be rapidly fatal if not, treated in time
 * Bowel and/or peritoneum
 * Pericardium (membrane around the heart)
 * Skin

Disseminated tuberculosis
Disseminated TB, also referred to as miliary tuberculosis, is TB infection in several different organs simultaneously.Technically extrapulmonary TB is any TB infection outside the lungs, while miliary TB indicates a widespread infection outside the lungs. In practice, the terms extrapulmonary, miliary, and disseminated are often used interchangeably.

Signs and Symptoms
The symptoms of extra-pulmonary tuberculosis depend on the site(s) if infection.

In lymphadenitis, the lymph glands become swollen painful and may have a rubbery texture. Abscesses may form in the lymph glands and discharge onto the skin giving a very unsightly combination of swelling and pus around the neck.

Osteo-TB or TB in the bones and joints, causes pain and swelling of the affected part. Spinal disease may cause paraplegia if enough of the vertebrae are destroyed to cause instability of the spine.

In tuberculous meningitis the symptoms usually begin gradually. Tuberculous meningitis may cause a wide variety of symptoms, including double vision and mental confusion developing over days or weeks. Patients may present with a headache that is either intermittent or persistent for 2-3 weeks. If not detected and treated coma may develop. If treated soon enough recovery may be complete but long term complications (sequelae) are likely if the treatment is delayed. TB meningitis has the highest mortality of all complications of tuberculosis.Subtle mental status changes may progress to coma over a period of days to weeks. Fever may be low-grade or absent.

Abdominal disease characteristically causes pain and constipation. If advanced it may cause complete obstruction of the bowel.

Reported symptoms for genito-urinary TB include; flank pain, painful urination, or urination frequency problems. In men, genital TB may present as epididymitis or a scrotal mass. In women, genital TB may mimic pelvic inflammatory disease.

Causes
Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis. The lungs are the usual route of infection. When someone with TB infection coughs, sneezes, or talks, tiny droplets of saliva or mucus are expelled into the air, which could be inhaled by another person. Once infectious particles reach the alveoli, small sacs in your lungs, another cell called the macrophage engulfs the TB bacteria. Then the bacteria can be transmitted to your lymph system and bloodstream and spread to other organs. The bacterium Mycobacterium tuberculosis is a member of the mycobacteria family. These bacteria are unusual in several respects. They grow slowly, have a unique type of cell wall with a high lipid (or fat) content. These characteristics mean that they are generally resistant to many antibiotics (like penicillins), and also that they can more easily become immune or resistant to antibiotics that do work against them. These drug resistant TB bacteria are a growing problem throughout the world.

Diagnosis
Tissue and/or fluids from the suspected site of infection are collected and used in the diagnostic tests. Some of the more common types of specimens in extrapulmonary TB diagnostics are: biopsy tissue, pleural fluids, peritoneal fluid, needle aspirates, cerebro-spinal fluid, and urine. Like pulmonary TB, extrapulmonary TB relies on a specialized bacterial stain and culture called acid-fast stain. Methods using molecular methods, such as PCR, are also often used in diagnosing extrapulmonary TB. The sensitivity of these methods is often crucial since few bacteria may be present in extrapulmonary TB.

Treatment
Treatment is as for pulmonary disease with isoniazid (INH), rifampicin, pyrazinamide and ethambutol for two months followed by isoniazid and pyrazinamide for four months, except for CNS disease when treatment should be continued for a full year. Steroids may be used in pericardial and meningeal disease. Surgery is usually unnecessary especially where lymph glands and abscess are present as long term discharging sinuses may result. Surgery is sometimes necessary in spinal TB where there is instability and may be needed to overcome strictures in GU or GI disease.

Drug resistant
Although drugs to treat TB have only been used for the last 50 years, strains of TB resistant to a single drug are relatively common. Drug-resistant TB is caused by inconsistent or partial treatment, when patients do not take all their medicines regularly for the required period because they start to feel better, because doctors and health workers prescribe the wrong treatment regimens, or because the drug supply is unreliable. A particularly dangerous form of drug-resistant TB is multidrug-resistant TB (MDR-TB), which is defined as the disease caused by TB bacteria resistant to at least isoniazid (INH) and rifampicin, the two most powerful anti-TB drugs. Rates of MDR-TB are high in some countries, especially in countries of the former Soviet Union, and threaten TB control efforts.

While drug-resistant TB is treatable, it requires extensive chemotherapy (up to two years of treatment) with second-line anti-TB drugs which are more costly than first-line drugs, and which produce adverse drug reactions that are more severe, though manageable.

The emergence of extensively drug-resistant (XDR) TB, particularly in settings where many TB patients are also infected with HIV, poses a serious threat to public health. XDR-TB are resistant to INH and rifampicin and also one or more of the second-line TB drugs.

BCG vaccine
BCG, or bacille Calmette and Guérin, is a vaccine for tuberculosis (TB) disease. BCG is a live, attenuated vaccine; this means it is a live organism similar to Mycobacterium tuberculosis. BCG is used in many countries, in fact, it is one of the most frequently administered vaccines in the world. Unlike other vaccines, it does not prevent the vaccinated from getting TB. However, it does protect children who contract TB from developing tuberculous meningitis and other types of extra-pulmonary TB. Some countries use BCG on newborns, others at older ages. The United Kingdom had a universal BCG vaccination for 13 year-olds until it was discontinued in 2005.

Although the BCG vaccine is not in general use in the United States, many foreign-born persons have been BCG-vaccinated. BCG vaccination may cause a positive reaction to the tuberculin skin test (TST), which may complicate decisions about prescribing treatment.

BCG is not recommended for general use in the United States because of the low risk of infection with Mycobacterium tuberculosis, the variable effectiveness of the vaccine against adult pulmonary TB, and the vaccine’s potential interference with tuberculin skin test reactivity. The BCG vaccine should be considered only for very select persons who meet specific criteria.

BCG immunotherapy in bladder cancer
An interesting use of the BCG vaccine is in bladder cancer treatment. BCG has been in use since the 1980's, and is the most proven and effective form of immunotherapy at this point in time. Immunotherapy has a mechanism of action different from that of chemotherapy. It uses materials made by your own body or made in a laboratory to boost, direct, or restore your body's natural defenses against disease.

BCG is instilled directly into the bladder. Although it is not yet totally understood why BCG and other immunotherapies work against cancer, they are thought to elicit an immune response. BCG has resulted in complete tumor regression in most patients.

Though side effects vary with the individual, the great majority of people find BCG treatments tolerable with side effects being temporay, and some have no adverse reactions at all.

Since BCG is a live vaccine, M. bovis can be isolated from the urine of people treated with BCG immunotherapy.

Chances of Developing
The bacteria that cause TB, M. tuberculosis, are spread through respiratory droplets and so the lungs are almost always the primary site of infection. People who have never been exposed to TB and not at risk for developing extrapulmonary TB, only people exposed to TB who have an untreated latent TB infection are at risk for extrapulmonary TB.

Risk factors
Risk factors for TB include the following:


 * HIV infection
 * Low socioeconomic status
 * Alcoholism
 * Homelessness
 * Crowded living conditions
 * Diseases or drugs that weaken the immune system
 * Residency or travel in a high-incidence country
 * Health care workers
 * Cancer
 * Transplantation
 * Malnutrition
 * Diabetes
 * Silicosis
 * Major surgical procedures may occasionally may trigger dissemination

How is Spread
TB is spread through the air from one person to another. The bacteria are put into the air when a person with active TB disease of the lungs or throat coughs or sneezes. People nearby may breathe in these bacteria and become infected.

When a person breathes in TB bacteria, the bacteria can settle in the lungs and begin to grow. From there, they can move through the blood to other parts of the body, such as the kidney, spine, and brain.

TB in the lungs or throat can be infectious. This means that the bacteria can be spread to other people. TB in other parts of the body, such as the kidney or spine, is usually not infectious.

People with active TB disease are most likely to spread it to people they spend time with every day. This includes family members, friends, and coworkers.

Comorbidity
People who are infected with HIV are especially susceptible to developing active tuberculosis (TB). TB is the leading cause of death among people living with HIV/AIDS and one of the most common opportunistic infections they experience. The prevalence of HIV infection among patients in TB clinical settings is high, up to 80 percent in some countries. Worldwide, TB is a leading cause of death among persons infected with HIV.

As of 2005, CDC estimated that 9% of all TB cases and nearly 16% of TB cases among persons aged 25 to 44 were occurring in HIV-infected persons. Because HIV infection so severely weakens the immune system, persons dually infected with HIV and TB, compared with persons not infected with HIV, are at very high risk for active TB disease, which may be contagious. Of the TB patients reported (in 2005) to be infected with HIV, 63% were non-Hispanic blacks.

This high level of risk underscores the need for TB screening and preventive treatment programs for HIV-infected persons and those at greatest risk for HIV infection. Everyone infected with HIV should be tested for TB. Everyone infected with TB should complete preventive therapy as soon as possible to prevent progression to TB disease.

People undergoing treatment for cancer often have their immune systems suppressed, this sometimes leads to reactivation of a latent tuberculosis infection.

Related disorders
Several diseases caused by bacteria related to Mycobacterium tuberculosis can mimic the symptoms of TB, although they are not transmitted from person-to-person like TB. The two most commonly seen diseases are atypical tuberculosis and bovine tuberculosis. Atypical tuberculosis is caused by other species of Mycobacteria, especially Mycobacterium avium complex or MAC. Atypical tuberculosis is most commonly seen in the elderly and immunocompromised.

Bovine tuberculosis
Bovine tuberculosis is caused by Mycobacterium bovis, a bacterium related to Mycobacterium tuberculosis that causes TB-like disease in cows. Before milk was routinely pasteurized cattle infected with ‘’M. bovis’’ could pass disease to humans who drank infected milk. Transmission by this route gives rise to a gastrointestinal form of TB. The increased consumption of organic and “natural” foods has resulted in several outbreaks of bovine-TB in the US in recent years. M. bovis is also the base for the vaccine strain BCG.

Expected Outcome
With treatment TB is a curable disease. Latent TB is cured by the standard 9 month therapy in more than 96% of cases. Treatment failure is almost always due to patient's not completing the full course of treatment.

MDR-TB is also curable, but antibiotic therapy often continues for two years or more.

History
See History in tuberculosis article.

Global impact
Although, the incidence in the Unites States and some other developed countries is low, one-third of the world's population, about 2 billion people, are infected with tuberculosis. Most of these are latent TB, but 200 million will become active in any given year.

Multi-drug resistant TB is very rare in countries (like the US) the use DOTS for treatment. But is becoming a serious problem in parts of the world where incomplete treatment and empiric therapy (treatment without drug-susceptibility testing) are common. Although MDR-TB occurs globally, it appears to be rare compared to drug-sensitive TB. XDR-TB is of particular concern among HIV-infected or other immunocompromised persons.

Interesting Facts
Here are some interesting facts regarding tuberculosis :


 * Every second, someone in the world is newly infected with TB.
 * Nearly one percent of the world's population is newly infected with TB each year.
 * 200 million people worldwide, or 10% of those infected, will develop active TB and be able to infect others for 3 decades.
 * 6 - 8 million news cases of TB are diagnosed each year.
 * In the last 100 years, 200 million people have died of TB.
 * TB kills 8,000 people a day - that is 2-3 million people each year. It kills more people than either AIDS or malaria. In fact, TB is the biggest killer of young people and adults in the world today.
 * TB spreads through the air and is highly contagious. On average, a person with infectious TB infects 10-15 others every year.
 * People infected with TB do not necessarily become ill - the immune system creates a barrier around the bacilli that can remain dormant for years. 10% of infected people (who do not have HIV/AIDS) develop active TB at some point during their lifetime.
 * Many notable people from the past had tuberculosis and many died of the disease . Some novels like Dumas The Lady of the Camellias that also became the opera La Traviata, were inspired on people with tuberculosis.

Notable experts
National Jewish Medical and Research Center

Francis J. Curry National TB Center

New Jersey Medical Center: Global TB Institute

Public Health
Like pulmonary TB, extrapulmonary TB requires notification of local public health authorities and proper infection control measures. Usually, public health authorities will try to determine if family members or close associated of extrapulmonary TB have been exposed to the TB bacteria. Often, however, the extrapulmonary TB is due to a reactivation of dormant M. tuberculosis. The primary infection may have taken place years or decades earlier.