Tuberculosis, MTB or TB (short for tubercles bacillus) is a common and in some cases deadly infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis in humans. Tuberculosis usually attacks the lungs but can also affect other parts of the body. It is spread through the air when people who have an active MTB infection cough, sneeze, or otherwise transmit their saliva through the air. Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progresses to active disease, which, if left untreated, kills more than 50% of its victims.
The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss (the last giving rise to the formerly prevalent colloquial term "consumption"). Infection of other organs causes a wide range of symptoms. Diagnosis relies on radiology (commonly chest X-rays), a tuberculin skin test, blood tests, as well as microscopic examination and microbiological culture of bodily fluids. Treatment is difficult and requires long courses of multiple antibiotics. Contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in (extensively) multi-drug-resistant tuberculosis. Prevention relies on screening programs and vaccination, usually with Bacillus Calmette-Guérin vaccine.
One third of the world's population is thought to be infected with M. tuberculosis, and new infections occur at a rate of about one per second. The proportion of people who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing. In 2007 there were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths, mostly in developing countries. In addition, more people in the developed world contract tuberculosis because their immune systems are more likely to be compromised due to higher exposure to immunosuppressive drugs, substance abuse, or AIDS. The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the US population test positive.
When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the lungs. Symptoms include chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, pallor, and fatigue. Tuberculosis also has a specific odour attached to it, enabling the use of trained animals to vet samples as a method of early detection.
In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura in tuberculosis pleurisy, the central nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Extrapulmonary TB may co-exist with pulmonary TB as well.
Persons with silicosis have an approximately 30-fold greater risk for developing TB. Silica particles irritate the respiratory system, causing immunogenic responses such as phagocytosis, which, as a consequence, results in high lymphatic vessel deposits. It is this interference and blockage of macrophage function that increases the risk of tuberculosis. Persons with chronic renal failure and also on hemodialysis have an increased risk. Persons with diabetes mellitus have a risk for developing active TB that is two to four times greater than persons without diabetes mellitus, and this risk is likely to be greater in persons with insulin-dependent or poorly controlled diabetes. Other clinical conditions that have been associated with active TB include gastrectomy with attendant weight loss and malabsorption, jejunoileal bypass, renal and cardiac transplantation, carcinoma of the head or neck, and other neoplasms (e.g., lung cancer, lymphoma, and leukemia).
Given that silicosis greatly increases the risk of tuberculosis, more research about the effect of various indoor or outdoor air pollutants on the disease would be necessary. Some possible indoor sources of silica include paint, concrete and Portland cement. Crystalline silica is found in concrete, masonry, sandstone, rock, paint, and other abrasives. The cutting, breaking, crushing, drilling, grinding, or abrasive blasting of these materials may produce fine silica dust. It can also be in soil, mortar, plaster, and shingles. When you wear dusty clothing at home or in your car, you may be carrying silica dust that your family will breathe.
Low body weight is associated with risk of tuberculosis as well. A body mass index (BMI) below 18.5 increases the risk by 2—3 times. On the other hand, an increase in body weight lowers the risk. Patients with diabetes mellitus are at increased risk of contracting tuberculosis, and they have a poorer response to treatment, possibly due to poorer drug absorption.
The correlation between diabetes mellitus and TB is concerning for public health because it shows a distinct connection between a contagious disease and a chronic disease. TB is a highly contagious air-born bacteria, therefore contracting tuberculosis depends on whether the patent comes into contact with the bacteria or not. Diabetics do not have an increased risk of contracting latent tuberculosis but studies have shown that patients with diabetes mellitus are more likely to move from a latent form of TB to an active form of TB. This is where the public concern comes from, because when TB is active it is contagious and potentially fatal.
Other conditions that increase risk include the sharing of needles among IV drug users; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; prolonged corticosteroid therapy and other immunosuppressive therapy; Immunocompromised patients (30–40% of AIDS patients in the world also have TB) hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass; chronic malabsorption syndromes; vitamin D deficiency; and low body weight.
Twin studies in the 1940s showed that susceptibility to TB was heritable. If one of a pair of twins got TB, then the other was more likely to get TB if he was identical than if he was not. These findings were more recently confirmed by a series of studies in South Africa. Specific gene polymorphisms in IL12B have been linked to tuberculosis susceptibility.
Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.
Mechanism
When people suffering from active pulmonary TB cough, sneeze, speak, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze can release up to 40,000 droplets. Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and inhaling fewer than ten bacteria may cause an infection.
People with prolonged, frequent, or intense contact are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year. Others at risk include people in areas where TB is common, people who inject drugs using unsanitary needles, residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.
Transmission can only occur from people with active — not latent — TB. The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain. The chain of transmission can, therefore, be broken by isolating patients with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious. If someone does become infected, then it will take at least 21 days, or three to four weeks, before the newly infected person can transmit the disease to others. TB can also be transmitted by eating meat infected with TB. Mycobacterium bovis causes TB in cattle. (See details below.)
About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease. However, if untreated, the death rate for these active TB cases is more than 50%.
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within the endosomes of alveolar macrophages. The primary site of infection in the lungs is called the Ghon focus, and is generally located in either the upper part of the lower lobe, or the lower part of the upper lobe. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to other tissues and organs where secondary TB lesions can develop in other parts of the lung (particularly the apex of the upper lobes), peripheral lymph nodes, kidneys, brain, and bone. All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.
Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system.
Importantly bacteria inside the granuloma can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of abnormal cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.
If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. Patients with this disseminated TB have a fatality rate near 100% if untreated. However, If treated early, the fatality rate is reduced to near 10%.
In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.
If untreated, infection with Mycobacterium tuberculosis can become lobar pneumonia.
Prevention of Tuberculosis
TB prevention and control takes two parallel approaches. In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB. No vaccine is available that provides reliable protection for adults. However, in tropical areas where the levels of other species of mycobacteria are high, exposure to nontuberculous mycobacteria gives some protection against TB.
The World Health Organization (WHO) declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between 2006 and 2015. Since humans are the only host of Mycobacterium tuberculosis, eradication would be possible. This goal would be helped greatly by an effective vaccine.
Many countries use Bacillus Calmette-Guérin (BCG) vaccine as part of their TB control programmes, especially for infants. According to the WHO, this is the most often used vaccine worldwide, with 85% of infants in 172 countries immunized in 1993. One country that notably does not widely administer BCG is the United States, where TB is rather uncommon. BCG was the first vaccine for TB. From 1905, Albert Calmette and Camille Guérin worked at the Institut Pasteur de Lille and the Pasteur Institute in France developing BCG, administering the first human trials in 1921. However, deaths due to flawed manufacturing processes created public resistance to BCG, delaying mass vaccinations until after World War II. The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.
In South Africa, the country with the highest prevalence of TB, BCG is given to all children under age three. However, BCG is less effective in areas where mycobacteria are less prevalent; therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:
* Infants or children with negative skin test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
* Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.
BCG provides some protection against severe forms of pediatric TB, but has been shown to be unreliable against adult pulmonary TB, which accounts for most of the disease burden worldwide. Currently, there are more cases of TB on the planet than at any other time in history and most agree there is an urgent need for a newer, more effective vaccine that would prevent all forms of TB—including drug resistant strains—in all age groups and among people with HIV.
Several new vaccines to prevent TB infection are being developed, among others by Aeras and TBVI. The first recombinant tuberculosis vaccine rBCG30, entered clinical trials in the United States in 2004, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans. A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University, and is based on a genetically modified vaccinia virus. Many other strategies are also being used to develop novel vaccines, including both subunit vaccines (fusion molecules composed of two recombinant proteins delivered in an adjuvant) such as Hybrid-1, HyVac4 or M72, and recombinant adenoviruses such as Ad35. Some of these vaccines can be effectively administered without needles, making them preferable for areas where HIV is very common. All of these vaccines have been successfully tested in humans and are now in extended testing in TB-endemic regions. To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.
January 2011: Statens Serum Institute in Denmark has announced in the journal Nature Medicine that a new vaccine can fight tuberculosis before and after infection. It has been applied in mice successfully. A tuberculosis vaccine aimed at sterile Mtb eradication should be able to target latent Mtb as well as Mtb that causes early-stage tuberculosis. The vaccine is a combination of antigens Ag85B and ESAT-6 as well as the protein Rv2660c. Ag85B and ESAT-6 together form the vaccine Hybrid-1, while Rv2660c is a protein that is expressed even in late-stage infections, when protein transcription is generally reduced. The novel combination of Ag85B, ESAT-6, and Rv2660c allows for both short- and long-term protection as a result of the continued expression of target proteins. The new vaccine, currently referred to as H56, works by promoting a polyfunctional CD4+ T cell response against tuberculosis protein components. Phase I clinical trials are scheduled to begin in Cape Town, South Africa in March 2011.
Treatment
Treatment for TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the unusual structure and chemical composition of the mycobacterial cell wall, which makes many antibiotics ineffective and hinders the entry of drugs. The two antibiotics most commonly used are isoniazid and rifampicin. However, instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 24 months) to entirely eliminate mycobacteria from the body. Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance. People with latent infections are treated to prevent them from progressing to active TB disease later in life.
Drug-resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance occurs in persons infected with a resistant strain of TB. A patient with fully susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low-quality medication. Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.
The DOTS (Directly Observed Treatment Short-course) strategy of tuberculosis treatment recommended by WHO was based on clinical trials done in the 1970s by Tuberculosis Research Centre, Chennai, India. The country in which a person with TB lives can determine what treatment they receive. This is because multidrug-resistant tuberculosis is resistant to most first-line medications, the use of second-line antituberculosis medications is necessary to cure the patient. However, the price of these medications is high; thus poor people in the developing world have no or limited access to these treatments.
In the early 1900s to 1950's doctors would try to collapse the infected lung by breaking several ribs or inflating that half of the chest with air.
History of tuberculosis
Consumption, phthisis, scrofula, Pott's disease, and the White Plague are all terms used to refer to tuberculosis throughout history. Although it is estimated to have existed 15,000 and 20,000 years, it is generally accepted that the microorganism originated from other, more primitive organisms of the same genus Mycobacterium. It is believed that at some point in its evolution, some species of the bacteria was able to invade animal hosts. This possibly took place with the first species Mycobacterium bovis, which is considered by most to be the oldest of the species that make up the Mycobacterium tuberculosis complex. M. bovis eventually passed to humans at a time coinciding with the domestication of animals. Human bones from the Neolithic show a presence of the bacteria although the exact magnitude (incidence and prevalence) is not known before the 19th century. Still, it is estimated that it reached its peak (with regard to the percentage of the population affected) between the end of the 18th century and the end of the 19th century. Over time, the various cultures of the world gave the illness different names: yaksma (India), phthisis (Greek), consumptione (Latin) and chaky oncay (Incan), each of which make reference to the "drying" or "consuming" affect of the illness, cachexia. Its high mortality rate among middle-aged adults and the surge of Romanticism, which stressed feeling over reason, caused many to refer to the disease as the "romantic disease."
Tuberculosis is one of the three primary diseases of poverty along with AIDS and malaria. The Global Fund to Fight AIDS, Tuberculosis and Malaria was started in 2002 to raise finances to address these infectious diseases. Globalization has led to increased opportunities for disease spread. A tuberculosis scare occurred in 2007 when Andrew Speaker flew on a transatlantic flight infected with multi-drug-resistant tuberculosis.
Globally, the World Health Organization and its Stop TB strategy are leading public health efforts to reduce the global burden of tuberculosis by 2015. In the United States, the National Center for HIV, STD, and TB Prevention, as part of the Centers for Disease Control and Prevention (CDC), is responsible for public health surveillance and prevention research.
