Tuberculosis

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Tuberculosis is an infection caused by the bacterium Mycobacterium tuberculosis, which most commonly affects the lungs (pulmonary TB) but can also affect the central nervous system (meningitis), lymphatic system, circulatory system (Miliary tuberculosis), genitourinary system, bones and joints.

Tuberculosis is the most common major infectious disease today, infecting two billion people or one-third of the world's population, with nine million new cases of active disease annually, resulting in two million deaths, mostly in developing countries.

Most of those infected (90 percent) have asymptomatic latent TB infection (LTBI). There is a 10 percent lifetime chance that LTBI will progress to active TB disease which, if left untreated, will kill more than 50 percent of its victims. TB is one of the top three infectious killing diseases in the world: HIV/AIDS kills 3 million people each year, TB kills 2 million, and malaria kills 1 million.

The neglect of TB control programs, HIV/AIDS, and immigration has caused a resurgence of tuberculosis. Multiple drug resistant strains of TB (MDR-TB) are emerging. The World Health Organization declared TB a global health emergency in 1993.

Contents

Other names for the disease

  • TB (short for tuberculosis and also for Tubercle Bacillus)
  • Consumption (TB seemed to consume people from within with its symptoms of bloody cough, fever, pallor, and long relentless wasting)
  • Wasting disease
  • White plague (TB sufferers appeared markedly pale)
  • Phthisis (Greek for consumption) and phthisis pulmonalis
  • Scrofula (swollen neck glands)
  • King's evil (so called because it was believed that a king's touch would heal scrofula)
  • Pott's disease of the spine
  • Miliary TB (x-ray lesions look like millet seeds)
  • Tabes mesenterica (TB of the abdomen)
  • Lupus vulgaris (the common wolf - TB of the skin)
  • Prosector's wart, also a kind of TB of the skin, transmitted by contact with contaminated cadavers to anatomists, pathologists, veterinarians, surgeons, butchers, etc.

The bacterium

File:TB AFB smear.jpg
Acid-fast bacilli (AFB) (shown in red) are tubercle bacilli Mycobacterium tuberculosis.

The cause of tuberculosis, Mycobacterium tuberculosis (MTB), is a slow-growing aerobic bacterium that divides every 16 to 20 hours. This is extremely slow compared to other bacteria, which tend to have division times measured in minutes (among the fastest growing bacteria is a strain of E. coli that can divide roughly every 20 minutes). It is not classified as either Gram-positive or Gram-negative because it does not have the chemical characteristics of either, although it contains peptidoglycan in their cell wall. If a Gram stain is performed, it stains very weakly Gram-positive or not at all. It is a small rod-like bacillus which can withstand weak disinfectants and can survive in a dry state for weeks but, spontaneously, can only grow within a host organism (in vitro culture of M. tuberculosis took a long time to be achieved, but is nowadays a normal laboratory procedure).

MTB is identified microscopically by its staining characteristics: it retains certain stains after being treated with acidic solution, and is thus classified as an "acid-fast bacillus" or "AFB". In the most common staining technique, the Ziehl-Neelsen stain, AFB are stained a bright red which stands out clearly against a blue background. Acid-fast bacilli can also be visualized by fluorescent microscopy, and by auramine-rhodamine stain.

The M. tuberculosis complex includes 3 other mycobacteria which can cause tuberculosis: M. bovis, M. africanum, and M. microti. The first two are very rare causes of disease and the last one does not cause human disease.

Nontuberculous mycobacteria (NTM) are other mycobacteria (besides M. leprae which causes leprosy) which may cause pulmonary disease resembling TB, lymphadenitis, skin disease, or disseminated disease. These include Mycobacterium avium, M. kansasii, and others.

The disease

Transmission

TB is spread through aerosol droplets which are expelled when persons with active TB disease cough, sneeze, speak, or spit. Close contacts (people with prolonged, frequent, or intense contact) are at highest risk of becoming infected (typically 22 percent infection rate but everything is possible, even up to 100%). A person with untreated, active tuberculosis can infect an estimated 20 other people per year. Others at risk include foreign-born from areas where TB is common, immunocompromised patients (eg. HIV/AIDS), residents and employees of high-risk congregate settings, health care workers who serve high-risk clients, medically underserved, low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, and people who inject illicit drugs.

Transmission can only occur from people with active TB disease (not latent TB infection).

The probability of transmission depends upon infectiousness of the person with TB (quantity expelled), environment of exposure, duration of exposure, and virulence of the organism.

The chain of transmission can be stopped by isolating patients with active disease and starting effective anti-tuberculous therapy.

Pathogenesis

While only 10 percent of TB infection progresses to TB disease, if untreated the death rate is 51 percent.

TB infection begins when MTB bacilli reach the pulmonary alveoli, infecting alveolar macrophages, where the mycobacteria replicate exponentially. Bacteria are picked up by dendritic cells, which can transport bacilli to local (mediastinal) lymph nodes, and then through the bloodstream to the more distant tissues and organs where TB disease could potentially develop: lung apices, peripheral lymph nodes, kidneys, brain, and bone.

Tuberculosis is classed 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 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. Within the granuloma, T lymphocytes secrete cytokine such as interferon gamma, which activates macrophages and make them better able to fight infection. T lymphocytes can also directly kill infected cells.

Importantly, bacteria are not eliminated with the granuloma, but can become dormant, resulting in a latent infection. Latent infection can be diagnosed only by tuberculin skin test, which yields a delayed hypertype sensitivity response to purified protein derivatives of M. tuberculosis in an infected person.

Another feature of the granulomas of human tuberculosis is the development of 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 blood stream from an area of tissue damage they spread through the body and set up myriad foci of infection, all appearing as tiny white tubercles in the tissues. This is called miliary tuberculosis and has a high case fatality.

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 in continuity with the air passages bronchi. This material may therefore be coughed up. It contains living bacteria and can pass on infection.

Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Affected areas are eventually replaced by scar tissue.

Progression

In those people in whom TB bacilli overcome the immune system defenses and begin to multiply, there is progression from TB infection to TB disease. This may occur soon after infection (primary TB disease – 1 to 5 percent) or many years after infection (post primary TB, secondary TB, reactivation TB disease of dormant bacilli – 5 to 9 percent). The risk of reactivation increases with immune compromise, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10 percent per year, while in immune competent individuals, the risk is between 5 and 10 percent in a lifetime.

About five percent of infected persons will develop TB disease in the first two years, and another five percent will develop disease later in life. In all, about 10 percent of infected persons with normal immune systems will develop TB disease in their lifetime.

Some medical conditions increase the risk of progression to TB disease. In HIV infected persons with TB infection, the risk increases to 10 percent each year instead of 10 percent over a lifetime. Other such conditions include drug injection (mainly because of the life style of IV Drug users), substance abuse, recent TB infection (within two years) or history of inadequately treated TB, chest X-ray suggestive of previous TB (fibrotic lesions and nodules), diabetes mellitus, silicosis, prolonged corticosteroid therapy and other immunosuppressive therapy, head and neck cancers, hematologic and reticuloendothelial diseases (leukemia and Hodgkin's disease), end-stage renal disease, intestinal bypass or gastrectomy, chronic malabsorption syndromes, or low body weight (10 percent or more below the ideal).

Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of causing a latent infection to become active due to the importance of this cytokine in the immune defense against TB.

TB disease most commonly affects the lungs (75 percent or more), where it is called pulmonary TB. Symptoms include a productive, prolonged cough of more than three weeks duration, chest pain, and hemoptysis. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, and easy fatigability. The term consumption arose because sufferers appeared as if they were "consumed" from within by the disease. People from Asian and African descent may have more often lymph node TB than Caucasians.

Extrapulmonary sites include the pleura, central nervous system (meningitis), lymphatic system (scrofula of the neck), genitourinary system, and bones and joints (Pott's disease of the spine). An especially serious form is "disseminated", or "miliary" TB, so named because the lung lesions so-formed resemble millet seeds on x-ray. These are more common in immunosuppressed persons and in young children. Pulmonary TB may co-exist with extrapulmonary TB.

Drug resistance

Drug-resistant TB is transmitted in the same way as drug-susceptible TB. Primary resistance develops in persons initially infected with resistant organisms. Secondary resistance (acquired resistance) may develop during TB therapy due to inadequate treatment regimen, not taking the prescribed regimen appropriately or using low quality medication.

Diagnosis

A complete medical evaluation for TB includes a medical history, a physical examination, a tuberculin skin test, a serological test, a chest X-ray, and microbiologic smears and cultures. The measurement of a positive skin test depends upon the person's risk factors for progression of TB infection to TB disease.

See: tuberculosis diagnosis, tuberculosis radiology

Treatment

Persons with TB infection (class 2 or class 4 TB), but who do not have TB disease (class 3 or class 5 TB), cannot spread the infection to other people. TB infection in a person who does not have TB disease is not considered a case of TB and is often referred to as latent TB infection (LTBI). This distinction is important because treatment options will be different for a person who has LTBI instead of active TB disease.

See: tuberculosis treatment

Prevention

Prevention and control efforts include three priority strategies:

  • identifying and treating all persons who have TB disease
  • finding and evaluating persons who have been in contact with TB patients to determine whether they have TB infection or disease, and treating them appropriately, and
  • testing high-risk groups for TB infection to identify candidates for treatment of latent infection and to ensure the completion of treatment.

In tropical areas where the incidence of atypical mycobacteria is high, exposure to nontuberculous mycobacteria gives some protection against TB.

BCG vaccine

Many countries use BCG vaccine as part of their TB control programs, especially for infants. The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is high (greater than 80 percent). However, the protective efficacy for preventing pulmonary TB in adolescents and adults is variable, from 0 to 80 percent. In the United Kingdom, children aged 10-14 were typically immunized during school until 2005. (Routine BCG vaccination was stopped as it was no longer cost-effective. The incidence of TB in people born in the UK, and with parents and grandparents who were born in the UK, was at an all time low, and falling. Others continue to be offered BCG vaccination.)

The effectiveness of BCG is much lower than in areas where mycobacteria are much less prevalent. In the USA, BCG vaccine is not routinely recommended except for selected persons who meet specific criteria:

  • Infants or children with negative skin-test result who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
  • Healthcare workers considered on individual basis in settings in which high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and not successful.

Tuberculosis vaccine

The first recombinant tuberculosis vaccine entered clinical trials in the United States in 2004 sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). [1]

A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protecting against re-infection in mice; it may take four to five years to be available in humans. PMID 15690060.

Because of the limitations of current vaccines, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.

Animals

Tuberculosis can be carried by many mammals. Domesticated species, such as cats and dogs, are generally free of tuberculosis, but wild animals may be carriers. As a result, many places have regulations restricting the ownership of novelty pets, possibly including such partially domesticated species as pet skunks; for example, the American state of California forbids the ownership of pet gerbils. The strictness of such restrictions generally depends on the public health policies adopted for fighting tuberculosis.

An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is underway. It has been found that herd infection is more likely in areas where infected vector species such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders. Controlling the vectors through possum eradication and monitoring the level of disease in livestock herds through regular surveillance are seen as a "two-pronged" approach to ridding New Zealand of the disease.

In both the Republic of Ireland and Northern Ireland, badgers have been identified as a vector species for the transmission of bovine tuberculosis. As a result, the government in both regions has mounted an active campaign of eradication of the species in an effort to reduce the incidence of the disease. Badgers have been culled primarily by snaring and gassing. It remains a contentious issue, with proponents and opponents of the scheme citing their own studies to support their position. [2] [3] [4]

History

Tuberculosis has been present in humans since antiquity, as the origins of the disease are in the first domestication of cattle (which also gave humanity viral poxes). Skeletal remains show prehistoric humans (4000 BC) had TB and tubercular decay has been found in the spines of Egyptian mummies from 3000-2400 BC. There were references to TB in India around 2000 BC and TB was present in The Americas from about 2000 BC

Phthisis is a Greek term for consumption. Around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times which was almost always fatal.

Due to the variety of its symptoms, TB was not identified as a unified disease until the 1820s and was not named tuberculosis until 1839 by J. L. Schönlein. During the years 1838-1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers into the cave in hopes of curing the disease with the constant temperature and purity of the cave air. The first TB sanatorium opened in 1859 in Poland, with another opening in the United States in 1885.

The bacillus-causing tuberculosis, Mycobacterium tuberculosis, was described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine for this discovery in 1905. Koch did not believe that bovine (cattle) and human tuberculosis were similar, which held back the recognition of infected milk as a source of infection. Later, this source was eliminated by pasteurization. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it tuberculin. It was not effective, but was later adapted by von Pirquet for a test for pre-symptomatic tuberculosis.

The first genuine success in immunizing against tuberculosis developed from attenuated bovine strain tuberculosis by Albert Calmette and Camille Guerin in 1906 was BCG (Bacillus of Calmette and Guerin). It was first used on humans on July 18, 1921 in France, although national arrogance prevented its widespread use in either the USA, Great Britain, or Germany until after World War II.

Tuberculosis caused the most widespread public concern in the 19th and early 20th centuries as the endemic disease of the urban poor. In 1815 England one in four deaths were of consumption; by 1918 one in six deaths in France were still caused by TB. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that rather resembled prisons. Whatever the purported benefits of the fresh air and labor in the sanatoria, 75% of those who entered were dead within five years (1908).

In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.

In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease's significance was still such that when the Medical Research Council was formed in Britain in 1913 its first project was tuberculosis.

It was not until 1946 with the development of the antibiotic streptomycin that treatment rather than prevention became a possibility. Prior to then only surgical intervention was possible as supposed treatment (other than sanatoria), including the pneumothorax technique: collapsing an infected lung to "rest" it and allow lesions to heal, which was an accomplished technique but was of little benefit and was discontinued after 1946.

Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, TB cases in Britain, numbering around 50,000 in 1955, had fallen to around 5,500 in 1987, but in 2001 there were over 7,000 confirmed cases. Due to the elimination of public health facilities in New York in the 1970s, there was a resurgence in the 1980s. The number of those failing to complete their course of drugs was very high. NY had to cope with more than 20,000 "unnecessary" TB-patients with many multi-drug resistant strains (i.e., resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.

In 2003, by disabling a set of genes, researchers accidentally created a more lethal and rapidly reproducing strain of tuberculosis bacteria.

Christmas Seals was started in 1904 in Denmark as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907-08 to help the National Tuberculosis Association, later called the American Lung Association.

During the Industrial Revolution, tuberculosis was more commonly thought of as vampirism. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that the cause of this was the original victim was draining the life from his/her family members. To cure this, people would dig up the body of what they thought was the vampire, open the chest and burn the heart, sometimes with the rest of the body. Furthermore, people who had TB exhibited symptoms similar to what people considered vampire traits (and may be where much of the common mythology of the vampire comes from). People with TB often had symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin and would cough blood (which people often figured needed to be replenished because of the loss in this manner, so they figured the only way to get blood back was by sucking blood).

Tuberculosis in art, literature, history and film

It has been speculated that the real-life ubiquity of illness and death due to tuberculosis affected the portrayal of these issues in European art and literature as well as history.

David Brainerd (born: April 20, 1718, died: October 9, 1747) only lived 29 years. His diary has been published and reflects his reliance upon God's faithfulness amidst his battle with consumption. Brainard's diary has proven historically very influential, particularly to the modern Christian missionary movement. He was a close friend of Theologian and Pastor Jonathan Edwards in New England. More information about Brainerd's life can be found detailed by contemporary pastor/theologian John Piper here[5], with Brainerd's diary being found here [6].

The Life and Death of Mr. Badman (1680) by John Bunyan - "Yet the captain of all these men of death that came against him to take him away, was the consumption, for it was that that brought him down to the grave."

The pale, "haunted" appearance of tuberculosis sufferers has been seen as an influence on the works of Edgar Allan Poe and in vampire tales. In recent years, this aesthetic has been revived by the "Goth" subculture.

The heroine, Mimi, of Puccini's opera La bohème suffers from tuberculosis (a theme carried over in the modern film adaptation Moulin Rouge!). Violetta, heroine of Verdi's La Traviata also dies of the disease.

In Jane Eyre by Charlotte Bronte, Jane's best friend in school dies of consumption. It is indicative of the horrible conditions of these types of schools in the 1800s.

In Sylvia Plath's novel The Bell Jar, the protagonist Esther's boyfriend Buddy Willard suffers from tuberculosis, much to her liking.

Celestine, the heroine of Octave Mirbeau's Diary of a Chambermaid, attempts to contract tuberculosis from her dying lover, Monsieur Georges.

In Nicholas Nickleby, by Charles Dickens, Nickleby's faithful companion Smike is beset by tuberculosis. In Bleak House, also by Charles Dickens, Richard Carstone dies of consumption.

Extensively, in The Magic Mountain, by Thomas Mann, where a three week visit to a sanitarium turns into a seven year sabbatical.

Tuberculosis patients were frequent characters in 19th century Russian literature, and even inspired a character type; the consumptive nihilist, examples of which include Bazarov from Ivan Turgenev's Fathers and Sons, Katerina Ivanovna from Fyodor Dostoevsky's Crime and Punishment, Kirillov from Dostoevsky's Demons (aka The Possessed), and Ippolit and Marie from Dostoevsky's The Idiot.

The hospitalized mother in the movie My Neighbor Totoro is thought to be suffering from tuberculosis (her ailment is not specifically named in the film, but tuberculosis is cited in the film's novelization). This is an autobiographical reference to the fact that writer/director Hayao Miyazaki's own mother spent several years of his childhood hospitalized with TB.

The Sick Child (1886) by Edvard Munch, portrait of his deceased sister Sophie who died of TB at 16. [7]

In Hocus Pocus by Kurt Vonnegut, the protagonist contracts TB later in his lifetime.

In "Long Day's Journey Into Night" by Eugene O'Neill character Edmund Tyrone is sick with consumption.

In the film "Moulin Rouge!", Satine (the beautiful courtesan) is dying from the disease.

In the film "Heavenly Creatures", directed by Peter Jackson, Juliet Hulme had TB, and her fear of being sent away 'for the good of her health' played a large role in determining the subsequent actions of herself and Pauline Parker.

In the Swedish Film "My Life as a Dog" the protagonist Ingemar deals with his mother suffering from TB.

In the Australian novel Seven Little Australians, Judy becomes consumptive after walking from the Blue Mountains to her home.

In the 2002 film The Twilight Samurai, the leading character Seibei Iguchi's wife dies of consumption at the beginning of the story. At the end, his opponent tells of the death of his own wife and daughter of consumption.

Famous gambler and gunslinger John "Doc" Holliday suffered from tuberculosis until his death in 1887. Doc and his bloody cough were masterfully portrayed by Val Kilmer in the 1993 film Tombstone.

Alice Neel (1900-1984), T.B. Harlem, 1940, American. Oil on canvas. JAMA cover June 8, 2005.

Legendary father of country music, Jimmie Rodgers (1897 - 1933) sang the woes of having tuberculosis in the song T.B. Blues (co-written with Raymond E. Hall). Rodgers ultimately died of the disease days after a New York city recording session.

Van Morrison's song "TB Sheets" (from the eponymous 1974 album) is about the narrator nursing a girl, who is dying of tuberculosis. The song is a reworking of the TB theme in American blues music.

The Catholic Church canonized Saint Therese of the Child Jesus (1873-1897) in 1925, who died of tuberculosis.

Holden Caulfield is sent to a sanitarium for potentially having TB in J.D. Salinger's Catcher in the Rye.

English Romantic poet John Keats (1795-1821) and some of his family were taken by tuberculosis.

In A Moveable Feast, Ernest Hemingway (1899-1961) recounts meeting Ernest Walsh, an Irish poet suffering from TB. "... I looked at him and his marked-for-death look and I thought, you con man conning me with your con."

The Vizier in the acclaimed, Prince of Persia: The Sands of Time is revealed to be suffering from the disease. He calls it by the name 'Consumption' and is the primary reason for his desire for the Dagger of Time's power.

See also

References

  • Core Curriculum on Tuberculosis: What the Clinician Should Know, 4th edition (2000). Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC). (Internet versionupdated Aug 2003).
  • Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Thorax 2000;55:887-901 (fulltext).
  • Thomas Dormandy (1999). The White Death: A History of Tuberculosis. ISBN 0814719279 HB - ISBN 1852853328 PB
  • Mountains Beyond Mountains: The Quest of Dr. Paul Farmer, a Man Who Would Cure the World. Tracy Kidder, Random House 2000. ISBN 0812973011. A nonfiction account of treating TB in Haiti, Peru, and elsewhere.
  • Ha SJ, Jeon BY, Youn JI, Kim SC, Cho SN, Sung YC. Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis. Gene Ther. 2005 Feb 03; [Epub ahead of print] PMID 15690060
  • Blumberg HM, Leonard MK Jr, Jasmer RM. Update on the treatment of tuberculosis and latent tuberculosis infection. JAMA 2005 Jun 8;293(22):2776-84. PMID 15941808
  • Nemery B, Yew WW, Albert R, Brun-Buisson C, Macnee W, Martinez FJ, Angus DC, Abraham E. Tuberculosis, nontuberculous lung infection, pleural disorders, pulmonary function, respiratory muscles, occupational lung disease, pulmonary infections, and social issues in AJRCCM in 2004. Am J Respir Crit Care Med. 2005 Mar 15;171(6):554-62. PMID 15753485

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