Tuberculosis

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Tuberculosis

Classification and external resources

Chest X-ray of a person with advanced tuberculosis. Infection in both lungs is marked by white arrow-heads, and the formation of a cavity is marked by black arrows.

ICD-10

A15A19

ICD-9

010018

OMIM

607948

DiseasesDB

8515

MedlinePlus

000077 000624

eMedicine

med/2324 emerg/618radio/411

MeSH

D014376

Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usuallyMycobacterium tuberculosis.[1] Tuberculosis typically attacks the lungs but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit their saliva through the air.[2] Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected. The classic symptoms of active TB infection are a chronic cough with blood-tinged sputum,fever, night sweats, and weight loss (the latter giving rise to the formerly prevalent term "consumption"). Infection of other organs causes a wide range of symptoms. Diagnosis of active TB relies on radiology (commonly chest X-rays) as well as microscopic examination and microbiological culture of body fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests. Treatment is difficult and requires administration of multiple antibiotics over a long period of time. Social contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in multiple drug-resistant tuberculosis (MDR-TB) infections. Prevention relies on screening programs and vaccinationwith the bacillus CalmetteGurin vaccine. One third of the world's population is thought to have been infected with M. tuberculosis,[3]with new infections occurring at a rate of about one per second.[3] In 2007, there were an estimated 13.7 million chronic active cases globally,[4] while in 2010 there were an estimated 8.8 million new cases and 1.5 million associated deaths, mostly occurring indeveloping countries.[5] The absolute number of tuberculosis cases has been decreasing since 2006, and new cases have decreased since 2002.[5] 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 510% of the United States population tests positive.[1] More people in the developing world contract tuberculosis because of compromised immunity, largely due to high rates of HIV infection and the corresponding development of AIDS.[6]
Contents
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1 Signs and symptoms

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1.1 Pulmonary 1.2 Extrapulmonary

2 Causes

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2.1 Mycobacteria 2.2 Risk factors

3 Mechanism

3.1 Transmission

3.2 Pathogenesis

4 Diagnosis

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4.1 Active tuberculosis 4.2 Latent tuberculosis

5 Prevention

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5.1 Vaccines 5.2 Public health

6 Management

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6.1 New onset 6.2 Recurrent disease 6.3 Medication resistance

7 Prognosis 8 Epidemiology 9 History 10 Society and culture 11 Research 12 In other animals 13 References 14 External links

Signs and symptoms

The main symptoms of variants and stages of tuberculosis are given, [7] with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.

About 510% of those without HIV, infected with tuberculosis, develop active disease during their lifetimes. [8] In contrast, 30% of those co-infected with HIV develop active disease.[8]Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary tuberculosis). [9] Extrapulmonary TB occurs when tuberculosis develops outside of the lungs. Extrapulmonary TB may co-exist with pulmonary TB as well.[9]General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue,[9] and significant finger clubbing may also occur.[8]

Pulmonary
If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).[6][10] Symptoms may include chest pain and a prolonged cough producing sputum. About 25% of people may not have any symptoms (i.e. they remain "asymptomatic").[6] Occasionally, people may cough up blood in small amounts, and in very rare cases the infection may erode into the pulmonary artery, resulting in massive bleeding (Rasmussen's aneurysm). Tuberculosis may become a chronic illness and cause extensive scarring in the upper lobes of the lungs. The upper lung lobes are more frequently affected by tuberculosis than the lower ones.[9] The reason for this difference is not entirely clear.[1] It may be due either to better air flow,[1] or to poor lymph drainage within the upper lungs.[9]

Extrapulmonary
In 1520% of active cases, the infection spreads outside the respiratory organs, causing other kinds of TB.[11] These are collectively denoted as "extrapulmonary tuberculosis".[12] Extrapulmonary TB occurs more commonly in immunosuppressed persons and young children. In those with HIV this occurs in more than 50% of cases.[12] Notable extrapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), thegenitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott's disease of the spine), among others. When it spreads to the bones, it is also known as "osseous tuberculosis".[13] a form of osteomyelitis.[1] A potentially more serious, widespread form of TB is called "disseminated" TB, commonly known as miliary tuberculosis.[9] Miliary TB makes up about 10% of extra pulmonary cases.[14]

Causes
Mycobacteria
Main article: Mycobacterium tuberculosis

Scanning electron micrograph ofMycobacterium tuberculosis

The main cause of TB is Mycobacterium tuberculosis, a small, aerobic nonmotile bacillus.[9]The high lipid content of this pathogen accounts for many of its unique clinical characteristics. [15] It divides every 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour.[16] Mycobacteria have an outer membrane lipid bilayer.[17] If a Gram stain is performed, MTB either stains very weakly "Gram-positive" or does not retain dye as a result of the high lipid and mycolic acid content of its cell wall.[18] MTB can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in the laboratory.[19] Using histological stains on expectorated samples from phlegm (also called "sputum"), scientists can identify MTB under a regular (light) microscope. Since MTB retains certain stains even after being treated with acidic solution, it is classified as an acid-fast bacillus(AFB).[1][18] The most common acid-fast staining techniques are the ZiehlNeelsen stain, which dyes AFBs a bright red that stands out clearly against a blue background,[20] and theauramine-rhodamine stain followed by fluorescence microscopy.[21] The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti.[22] M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa.[23][24] M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries.[1][25] M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants.[26][27] M. microti is also rare and is mostly seen in immunodeficient people, although the prevalence of this pathogen has possibly been significantly underestimated.[28] Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter two species are classified as "nontuberculous mycobacteria" (NTM). NTM cause neither TB nor leprosy, but they do cause pulmonary diseases that resemble TB.[29]

Risk factors

Main article: Risk factors for tuberculosis A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all TB cases are infected by the virus.[5] This is a particular problem in sub-Saharan Africa, where rates of HIV are high.[30][31] Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty.[6] Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients and health care providers serving these clients.[32] Chronic lung disease is another significant risk factor - withsilicosis increasing the risk about 30-fold.[33] Those who smoke cigarettes have nearly twice the risk of TB than non-smokers.[34] Other disease states can also increase the risk of developing tuberculosis, including alcoholism[6] and diabetes mellitus (threefold increase).[35] Certain medications, such as corticosteroids and infliximab (an anti-TNF monoclonal antibody) are becoming increasingly important risk factors, especially in the developed world.[6] There is also a genetic susceptibility[36] for which overall importance is still undefined.[6]

Mechanism

Public health campaigns in the 1920s tried to halt the spread of TB.

Transmission
When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5 m in diameter. A single sneeze can release up to 40,000 droplets.[37] Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low (the inhalation of fewer than 10 bacteria may cause an infection).[38] People with prolonged, frequent, or close contact with people with TB are at particularly high risk of becoming infected, with an estimated 22% infection rate.[39] A person with active but untreated tuberculosis may infect 10 15 (or more) other people per year.[3] Transmission should only occur from people with active TB - those with latent infection are not thought to be contagious.[1] The probability of transmission from one person to another depends upon several factors, including the number of infectious droplets expelled by the carrier, the effectiveness of ventilation, the duration of exposure, the virulence of the M. tuberculosisstrain, the level of immunity in the uninfected person, and others.[40] The cascade of person-to-person spread can be circumvented by effectively segregating those with active ("overt") TB and putting them on anti-TB drug regimens. After about two weeks of effective treatment, subjects with non-resistant active infections generally

do not remain contagious to others.[39]If someone does become infected, it typically takes three to four weeks before the newly infected person becomes infectious enough to transmit the disease to others. [41]

Pathogenesis
About 90% of those infected with M. tuberculosis have asymptomatic, latent TB infections (sometimes called LTBI),[42] with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease.[43] In those with HIV, the risk of developing active TB increases to nearly 10% a year.[43] If effective treatment is not given, the death rate for active TB cases is up to 66%.[3] TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within endosomes of alveolarmacrophages.[1][44] The primary site of infection in the lungs, known as the "Ghon focus", is generally located in either the upper part of the lower lobe, or the lower part of the upper lobe.[1] Tuberculosis of the lungs may also occur via infection from the blood stream. This is known as a Simon focus and is typically found in the top of the lung.[45] This hematogenous transmission can also spread infection to more distant sites such as peripheral lymph nodes, the kidneys, the brain, and the bones. [1][46] All parts of the body can be affected by the disease, though for unknown reasons it rarely affects the heart, skeletal muscles, pancreas, or thyroid.[47] Tuberculosis is classified as one of the granulomatous inflammatory diseases. Macrophages, T lymphocytes, B lymphocytes, andfibroblasts are among the cells that aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. The granuloma prevents dissemination of the mycobacteria and provides a local environment for interaction of cells of the immune system. Bacteria inside the granuloma can become dormant, resulting in latent infection. Another feature of the granulomas is the development of abnormal cell death (necrosis) in the center of tubercles. To the naked eye, this has the texture of soft, white cheese and is termedcaseous necrosis.[48] If TB bacteria gain entry to the bloodstream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the tissues.[49] This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis.[50] People with this disseminated TB have a high fatality rate even with treatment (about 30%).[14][51] In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis.[48] Affected tissue is replaced by scarring and cavities filled with caseous 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 so can spread the infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.[48]

Diagnosis
Main article: Tuberculosis diagnosis

Mycobacterium tuberculosis (stained red) in sputum

Active tuberculosis
Diagnosing active tuberculosis based merely on signs and symptoms is difficult, [52] as is diagnosing the disease in those who are immunosuppressed.[53] A diagnosis of TB should, however, be considered in those with signs of lung disease or constitutional symptomslasting longer than two weeks.[53] A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial evaluation.[53] Interferon- release assays and tuberculin skin tests are of little use in the developing world.[54][55] IGRA have similar limitations in those with HIV.[56][57] A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g.sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture.[58] Thus, treatment is often begun before cultures are confirmed.[59] Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB.[52] These tests, however, are not routinely recommended, as they rarely alter how a person is treated.[59] Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.[60]

Latent tuberculosis

Mantoux tuberculin skin test

The Mantoux tuberculin skin test is often used to screen people at high risk for TB.[53] Those who have been previously immunized may have a false-positive test result.[61] The test may be falsely negative in those with sarcoidosis, Hodgkin's lymphoma, malnutrition, or most notably, in those who truly do have active tuberculosis.[1] Interferon gamma release assays(IGRAs), on a blood sample, are recommended in those who are positive to the Mantoux test.[59] These are not affected by immunization or most environmental mycobacteria, so they generate fewer false-positive results.[62] However they are affected by M. szulgai, M. marinum and M. kansasii.[63] IGRAs may increase sensitivity when used in addition to the skin test but may be less sensitive than the skin test when used alone.[64]

Prevention
Tuberculosis prevention and control efforts primarily rely on the vaccination of infants and the detection and appropriate treatment of active cases.[6] The World Health Organization has achieved some success with improved treatment regimens, and a small decrease in case numbers.[6]

Vaccines
The only currently available vaccine as of 2011 is bacillus CalmetteGurin (BCG) which, while it is effective against disseminated disease in childhood, confers inconsistent protection against contracting pulmonary TB.[65] Nevertheless, it is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated.[6] However, the immunity it induces decreases after about ten years.[6] As tuberculosis is uncommon in most of Canada, the United Kingdom, and the United States, BCG is only administered to people at high risk.[66][67][68] Part of the reasoning arguing against the use of the vaccine is that it makes the tuberculin skin test falsely positive, and therefore, of no use in screening.[68] A number of new vaccines are currently in development.[6]

Public health
The World Health Organization declared TB a "global health emergency" in 1993,[6] and in 2006, the Stop TB Partnership developed aGlobal Plan to Stop Tuberculosis that aims to save 14 million lives between its launch and 2015.[69] A number of targets they have set are not likely to be achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis (MDRTB).[6] A tuberculosis classification system developed by the American Thoracic Society is used primarily in public health programs.[70]

Management
Main article: Tuberculosis management Treatment of 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 hinders the entry of drugs and makes many antibiotics ineffective.[71] The two antibiotics most commonly used are isoniazid and rifampicin, and treatments can be prolonged, taking upwards of several months.[40]Latent TB treatment usually employs a single antibiotic,[72] while active TB disease is best treated with combinations of several antibiotics to reduce the risk of the bacteria developing antibiotic resistance.[6] People with latent infections are also treated to prevent them from progressing to active TB disease later in life.[72] Directly observed therapy (DOTS), i.e. having a health care provider watch the person take their medications, is recommended by the WHO in an effort to reduce the number of people not appropriately taking antibiotics.[73] The evidence to support this practice over people simply taking their medications independently is poor.[74] Methods to remind people of the importance of treatment do however appear effective.[75]

New onset
The recommended treatment of new-onset pulmonary tuberculosis, as of 2010, is six months of a combination of antibiotics containing rifampicin, isoniazid, pyrazinamide and ethambutol for the first two months, and only

rifampicin and isoniazid for the last four months.[6]Where resistance to isoniazid is high, ethambutol may be added for the last four months as an alternative.[6]

Recurrent disease
If tuberculosis recurs, testing to determine to which antibiotics it is sensitive is important before determining treatment.[6] If multiple drug-resistant TB (MDR-TB) is detected, treatment with at least four effective antibiotics for 18 to 24 months is recommended.[6]

Medication resistance
Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible TB may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication.[76] Drugresistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is also resistant to three or more of the six classes of second-line drugs.[77] Totally drug-resistant TB, which was first observed in 2003 in Italy but not widely reported until 2012, is resistant to all currently used drugs.[78]

Prognosis
Progression from TB infection to overt TB disease occurs when the bacilli overcome the immune system defenses and begin to multiply. In primary TB disease (some 15% of cases) this occurs soon after the initial infection.[1] However, in the majority of cases, a latent infection occurs with no obvious symptoms.[1] These dormant bacilli produce active tuberculosis in 510% of these latent cases, often many years after infection.[8] The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In people co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.[1] Studies using DNA fingerprinting of M. tuberculosis strains have shown that reinfection contributes more substantially to recurrent TB than previously thought,[79] with estimates that it might account for more than 50% of reactivated cases in areas where TB is common.[80] The chance of death from a case of tuberculosis is about 4% as of 2008, down from 8% in 1995.[6]

Epidemiology
Main article: Epidemiology of tuberculosis

In 2007, the prevalence of TB per 100,000 people was highest in sub-Saharan Africa, and was also relatively high in Asia.[81]

Roughly one third of the world's population has been infected with M. tuberculosis, and new infections occur at a rate of one per second on a global scale.[3] However, most infections with M. tuberculosis do not cause TB disease,[82] and 9095% of infections remain asymptomatic.[42] In 2007, there were an estimated 13.7 million chronic active cases.[4] In 2010, there were 8.8 million new cases of TB diagnosed, and 1.45 million deaths, most of these occurring in developing countries.[5] Of these 1.45 million deaths, about 0.35 million occur in those coinfected with HIV.[83] Tuberculosis is the second most common cause of death from infectious disease (after those due to HIV/AIDS).[9] The absolute number of tuberculosis cases ("prevalence") has been decreasing since 2005, while new cases ("incidence") have decreased since 2002.[5]China has achieved particularly dramatic progress, with an approximate 80% reduction in its TB mortality rate between 1990 and 2010.[83] Tuberculosis is more common in developing countries; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 510% of the US population test positive.[1] Hopes of totally controlling the disease have been dramatically dampened because of a number of factors, including the difficulty of developing an effective vaccine, the expensive and time-consuming diagnostic process, the necessity of many months of treatment, the increase in HIV-associated tuberculosis, and the emergence of drug-resistant cases in the 1980s.[6]

Annual number of new reported TB cases. Data from WHO.[84]

In 2007, the country with the highest estimated incidence rate of TB was Swaziland, with 1,200 cases per 100,000 people. India had the largest total incidence, with an estimated 2.0 million new cases.[4] In developed countries, tuberculosis is less common and is found mainly in urban areas. Rates per 100,000 people in different areas of the world where: globally 178, Africa 332, the Americas 36, Eastern Mediterranean 173, Europe 63, South East Asia 278, and Western Pacific 139 in 2010.[83] In Canada and Australia, tuberculosis is many times more common among the aboriginal peoples, especially in remote areas.[85][86]In the United States the Aborigines have a five fold greater mortality from TB.[87] The incidence of TB varies with age. In Africa, it primarily affects adolescents and young adults.[88] However, in countries where incidence rates have declined dramatically (such as the United States), TB is mainly a disease of older people and the immunocompromised.[1][89]

History
Main article: History of tuberculosis

Egyptian mummy in the British Museum - tubercular decay has been found in the spines of Egyptian mummies.

Tuberculosis has been present in humans since antiquity.[6] The earliest unambiguous detection of M. tuberculosis involves evidence of the disease in the remains of bison dated to approximately 17,000 years ago.[90] However, whether tuberculosis originated in bovines, then was transferred to humans, or whether it diverged from a common ancestor, is currently unclear.[91] A comparison of the genes of M. tuberculosis complex (MTBC) in humans to MTBC in animals suggests that humans did not acquire MTBC from animals during animal domestication, as was previously believed. Both strains of the tuberculosis bacteria share a common ancestor, which could have infected humans as early as the Neolithic Revolution.[92] Skeletal remains show prehistoric humans (4000 BC) had TB, and researchers have found tubercular decay in the spines of Egyptian mummies dating from 30002400 BC.[93] "Phthisis" is a Greek word for consumption, an old term for pulmonary tuberculosis;[94] around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times. It was said to involve fever and the coughing up of blood, which was almost always fatal.[95] Genetic studies suggest TB was present in the Americas from about the year 100 AD.[96] Before the Industrial Revolution, folklore often associated tuberculosis with vampires. When one member of a family died from it, the other infected members would lose their health slowly. People believed this was caused by the original person with TB draining the life from the other family members.[97] Although the pulmonary form associated with tubercles was established as a pathology by Dr Richard Morton in 1689,[98][99] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s, and was not named tuberculosis until 1839 by J. L. Schnlein.[100] During the years 18381845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of people with tuberculosis into the cave in the hope of curing the disease with the constant temperature and purity of the cave air: they died within a year.[101] Hermann Brehmer opened the first TB sanatorium in 1859 in Sokoowsko, Poland.[102]

Dr. Robert Koch discovered the tuberculosis bacilli.

The bacillus causing tuberculosis, Mycobacterium tuberculosis, was identified and described on 24 March 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery.[103] Koch did not believe the bovine (cattle) and human tuberculosis diseases were similar, which delayed the recognition of infected milk as a source of infection. Later, the risk of transmission from this source was dramatically reduced by the invention of the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it 'tuberculin'. While it was not effective, it was later successfully adapted as a screening test for the presence of presymptomatic tuberculosis.[104]

Albert Calmette and Camille Gurin achieved the first genuine success in immunization against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It was called BCG (bacillus of Calmette and Gurin). The BCG vaccine was first used on humans in 1921 in France,[105] but only received widespread acceptance in the USA, Great Britain, and Germany after World War II.[106] Tuberculosis caused the most widespread public concern in the 19th and early 20th centuries as anendemic disease of the urban poor. In 1815, one in four deaths in England was due to "consumption". By 1918, one in six deaths in France was still caused by TB. After determining that the disease was contagious in the 1880s, TB was put on a notifiable disease list in Britain, campaigns were started to stop people from spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons (the sanatoria for the middle and upper classes offered excellent care and constant medical attention).[102] Whatever the (purported) benefits of the "fresh air" and labor in the sanatoria, even under the best conditions, 50% of those who entered died within five years (ca.1916).[102] In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths.[107] Mortality then decreased nearly 90% by the 1950s.[108] Improvements in public health began significantly reducing rates of tuberculosis even before the arrival of streptomycin and other antibiotics, although the disease remained a significant threat to public health such that when the Medical Research Council was formed in Britain in 1913, its initial focus was tuberculosis research.[109] In 1946, the development of the antibiotic streptomycin made effective treatment and cure of TB a reality. Prior to the introduction of this drug, the only treatment (except sanatoria) was surgical intervention, including the "pneumothorax technique", which involved collapsing an infected lung to "rest" it and allow tuberculous lesions to heal.[110] The emergence of MDR-TB has again introduced surgery as an option within the generally accepted standard of care in treating TB infections. Current surgical interventions involve removal of pathological chest cavities ("bullae") in the lungs to reduce the number of bacteria and to increase the exposure of the remaining bacteria to drugs in the bloodstream, thereby simultaneously reducing the total bacterial load and increasing the effectiveness of systemic antibiotic therapy.[111] Hopes of completely eliminating TB (cf. smallpox) were dashed after the rise of drug-resistant strains in the 1980s. The subsequent resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.[112]

Society and culture

The World Health Organization and the Bill and Melinda Gates Foundation are subsidizing a new fast-acting diagnostic test for use in low- and middle-income countries.[113][114] Many resource-poor places as of 2011 still only have access to sputum microscopy.[115]

India had the highest total number of TB cases worldwide in 2010, in part due to poor disease management within the private health care sector. Programs such as the Revised National Tuberculosis Control Program are helping to reduce TB levels amongst people receiving public health care.[116][117]

Research
The BCG vaccine has limitations, and research to develop new TB vaccines is ongoing. [118] A number of potential candidates are currently in phase I and II clinical trials.[118] Two main approaches are being used to attempt to improve the efficacy of available vaccines. One approach involves adding a subunit vaccine to BCG, while the other strategy is attempting to create new and better live vaccines.[118] MVA85A, an example of a subunit vaccine which is currently in trials in South Africa, is based on a genetically modifiedvaccinia virus.[119] Vaccines are hoped to play a significant role in treatment of both latent and active disease.[120] To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development, including prizes, tax incentives, and advance market commitments.[121][122] A number of groups, including the Stop TB Partnership,[123] the South African Tuberculosis Vaccine Initiative, and the Aeras Global TB Vaccine Foundation, are involved with research.[124] Among these, the Aeras Global TB Vaccine Foundation received a gift of more than $280 million (US) from the Bill and Melinda Gates Foundation to develop and license an improved vaccine against tuberculosis for use in high burden countries. [125][126]

In other animals
Mycobacteria infect many different animals, including birds,[127] rodents,[128] and reptiles.[129] The subspecies Mycobacterium tuberculosis, though, is rarely present in wild animals.[130] An effort to eradicate bovine tuberculosis caused by Mycobacterium bovisfrom the cattle and deer herds of New Zealand has been relatively successful.[131] Efforts in Great Britain have been less successful.[132][133]
INTRODUCTION Pulmonary tuberculosis is an infectious disease caused by slowgrowing bacteria that resembles a fungus, Myobacterium tuberculosis, which is usually spread from person to person by droplet nuclei through the air. The lung is the usual infection site but the disease can occur elsewhere in the body. Typically, the bacteria from lesion (tubercle) in the alveoli. The lesion may heal, leaving scar tissue; may continue as an active granuloma, heal, then reactivate or may progress to necrosis, liquefaction, sloughing, and cavitation of lung tissue. The initial lesion may disseminate bacteria directly to adjacent tissue, through the blood stream, the lymphatic system, or the bronchi. Most people who become infected do not develop clinical illness because the bodys immune system brings the infection under control. However, the incidence of tuberculosis (especially drug resistant varieties) is rising. Alcoholics, the homeless and patients infected with the human

immunodeficiency virus (HIV) are especially at risk. Complications of tuberculosis include pneumonia, pleural effusion, and extrapulmonary disease. ANATOMY AND PHYSIOLOGY

UPPER RESPIRATORY TRACT Respiration is defined in two ways. In common usage, respiration refers to the act of breathing, or inhaling and exhaling. Biologically speaking, respiration strictly means the uptake of oxygen by an organism, its use in the tissues, and the release of carbon dioxide. By either definition, respiration has two main functions: to supply the cells of the body with the oxygen needed for metabolism and to remove carbon dioxide formed as a waste product from metabolism. This lesson describes the components of the upper respiratory tract. The upper respiratory tract conducts air from outside the body to the lower respiratory tract and helps protect the body from irritating substances. The upper respiratory tract consists of the following structures: The nasal cavity, the mouth, the pharynx, the epiglottis, the larynx, and the upper trachea. The oesophagus leads to the digestive tract. One of the features of both the upper and lower respiratory tracts is the mucociliary apparatus that protects the airways from irritating substances, and is composed of the ciliated cells and mucus-producing glands in the nasal epithelium. The glands produce a layer of mucus that traps unwanted particles as they are inhaled. These are swept toward the posterior pharynx, from where they are either swallowed, spat out, sneezed, or blown out. Air passes through each of the structures of the upper respiratory tract on its way to the lower respiratory tract. When a person at rest inhales, air enters via the nose and mouth. The nasal cavity filters, warms, and humidifies air. The pharynx or throat is a tube like structure that connects the back of the nasal cavity and mouth to the larynx, a passageway for air, and the esophagus, a passageway for food. The pharynx serves as a common hallway for the respiratory and digestive tracts, allowing both air and food to pass through before entering the appropriate passageways. The pharynx contains a specialised flap-like structure called the epiglottis that lowers over the larynx to prevent the inhalation of food and liquid into the lower respiratory tract.

The larynx, or voice box, is a unique structure that contains the vocal cords, which are essential for human speech. Small and triangular in shape, the larynx extends from the epiglottis to the trachea. The larynx helps control movement of the epiglottis. In addition, the larynx has specialised muscular folds that close it off and also prevent food, foreign objects, and secretions such as saliva from entering the lower respiratory tract.

Tuberculosis: Pathophysiology, Clinical Features, and Diagnosis

1. Nancy A. Knechel, RN, MSN, ACNP +Author Affiliations 1. Nancy Knechel received a BSN from the University of Maryland, Baltimore, in 2003 and then worked in an emergency department in Sacramento, California. She received an MSN from the University of Pennsylvania in the acute care nurse practitioner program and now works at University of California, San Diego Medical Center, in the Division of Trauma. Corresponding author: Nancy A. Knechel, RN, MSN, ACNP, University of California, San Diego Medical Center, 200 W Arbor Dr, #8896, San Diego, CA 92103-8896 (e-mail: nknechel@ucsd.edu). This article has been designated for CE credit. A closed-book, multiple-choice examination follows this article, which tests your knowledge of the following objectives: 1. 2. 3. Identify 3 reasons why the prevalence of tuberculosis is continuing to increase List at least 2 diagnostic tests for tuberculosis Describe 2 medically challenging physiological characteristics of tuberculosis caused by the lipid barrier of mycobacteria.

1.

Tuberculosis is often underrecognized; the author describes how to obtain a definitive diagnosis of tuberculosis. Tuberculosis has recently reemerged as a major health concern. Each year, approximately 2 million persons worldwide die of tuberculosis and 9 million become infected.1 In the United States, approximately 14000 cases of tuberculosis were reported in 2006, a 3.2% decline from the previous year; however, 20 states and the District of Columbia had higher rates. 2 The prevalence of tuberculosis is continuing to increase because of the increased number of patients infected with human immunodeficiency virus, bacterial resistance to medications, increased international travel and immigration from countries with high prevalence, and the growing numbers of the homeless and drug abusers.3With 2 billion persons, a third of the world population,1 estimated to be infected with mycobacteria, all nurses, regardless of area of care, need to understand the pathophysiology, clinical features, and procedures for diagnosis of tuberculosis. The vulnerability of hospitalized patients to tuberculosis is often underrecognized because the infection is habitually considered a disease of the community. Most hospitalized patients are in a suboptimal immune state, particularly in intensive care units, making exposure to tuberculosis even more serious than in the community. By understanding the causative organism, pathophysiology, transmission, and diagnostics of tuberculosis and the clinical manifestations in patients, critical care nurses will be better prepared to recognize infection, prevent transmission, and treat this increasingly common disease. Next Section

Causative Organism
Tuberculosis is an infection caused by the rod-shaped, nonspore-forming, aerobic bacterium Mycobacterium tuberculosis.4 Mycobacteria typically measure 0.5 m by 3 m, are classified as acid-fast bacilli, and have a unique cell wall structure crucial to their survival. The well-developed cell wall contains a considerable amount of a fatty acid, mycolic acid, covalently attached to the underlying peptidoglycan-bound polysaccharide arabinogalactan, providing an extraordinary lipid barrier. This barrier is responsible for many of the medically challenging physiological characteristics of tuberculosis, including resistance to antibiotics and host defense mechanisms. The composition and quantity of the cell wall components affect the bacterias virulence and growth rate.5 The peptidoglycan polymer confers cell wall rigidity and is just external to the bacterial cell membrane, another contributor to the permeability barrier of mycobacteria. Another important component of the cell wall is lipoarabinomannan, a carbohydrate structural antigen on the outside of the organism that is immunogenic and facilitates the survival of mycobacteria within macrophages. 5,6 The cell wall is key to the survival of mycobacteria, and a more complete understanding of the biosynthetic pathways and gene functions and the development of antibiotics to prevent formation of the cell wall are areas of great interest. 6 Previous SectionNext Section

Transmission
Mycobacterium tuberculosis is spread by small airborne droplets, called droplet nuclei, generated by the coughing, sneezing, talking, or singing of a person with pulmonary or laryngeal tuberculosis. These minuscule droplets can remain airborne for minutes to hours after expectoration. 5 The number of bacilli in the droplets, the virulence of the bacilli, exposure of the bacilli to UV light, degree of ventilation, and occasions for aerosolization all influence transmission.7Introduction of M tuberculosis into the lungs leads to infection of the respiratory system; however, the organisms can spread to other organs, such as the lymphatics, pleura, bones/joints, or meninges, and cause extrapulmonary tuberculosis. Previous SectionNext Section

Pathophysiology
Once inhaled, the infectious droplets settle throughout the airways. The majority of the bacilli are trapped in the upper parts of the airways where the mucus-secreting goblet cells exist. The mucus produced catches foreign substances, and the cilia on the surface of the cells constantly beat the mucus and its entrapped particles upward for removal.8 This system provides the body with an initial physical defense that prevents infection in most persons exposed to tuberculosis.9 Bacteria in droplets that bypass the mucociliary system and reach the alveoli are quickly surrounded and engulfed by alveolar macrophages,7,8 the most abundant immune effector cells present in alveolar spaces. 10 These macrophages, the next line of host defense, are part of the innate immune system and provide an opportunity for the body to destroy the invading mycobacteria and prevent infection.11 Macrophages are readily available phagocytic cells that combat many pathogens without requiring previous exposure to the pathogens. Several mechanisms and macrophage receptors are involved in uptake of the mycobacteria. 11 The mycobacterial lipoarabinomannan is a key ligand for a macrophage receptor.12 The complement system also plays a role in the phagocytosis of the bacteria.13 The complement protein C3 binds to the cell wall and enhances recognition of the mycobacteria by macrophages. Opsonization by C3 is rapid, even in the air spaces of a host with no previous exposure to M tuberculosis.14 The subsequent phagocytosis by macrophages initiates a cascade of events that results in either successful control of the infection, followed by latent tuberculosis, or progression to active disease, called primary progressive tuberculosis.8 The outcome is essentially determined by the quality of the host defenses and the balance that occurs between host defenses and the invading mycobacteria.11,15 After being ingested by macrophages, the mycobacteria continue to multiply slowly,8 with bacterial cell division occurring every 25 to 32 hours.4,7 Regardless of whether the infection becomes controlled or progresses, initial development involves production of proteolytic enzymes and cytokines by macrophages in an attempt to degrade the bacteria.11,12 Released cytokines attract T lymphocytes to the site, the cells that constitute cell-mediated immunity. Macrophages then present mycobacterial antigens on their surface to the T cells. 11 This initial immune process continues for 2 to 12 weeks; the microorganisms continue to grow until they reach sufficient numbers to fully elicit the cell-mediated immune response, which can be detected by a skin test. 4,8,11

For persons with intact cell-mediated immunity, the next defensive step is formation of granulomas around the M tuberculosis organisms16 (Figure 1). These nodular-type lesions form from an accumulation of activated T lymphocytes and macrophages, which creates a micro-environment that limits replication and the spread of the mycobacteria.8,12 This environment destroys macrophages and produces early solid necrosis at the center of the lesion; however, the bacilli are able to adapt to survive.18 In fact, M tuberculosisorganisms can change their phenotypic expression, such as protein regulation, to enhance survival. 13 By 2 or 3 weeks, the necrotic environment resembles soft cheese, often referred to caseous necrosis, and is characterized by low oxygen levels, low pH, and limited nutrients. This condition restricts further growth and establishes latency. Lesions in persons with an adequate immune system generally undergo fibrosis and calcification, successfully controlling the infection so that the bacilli are contained in the dormant, healed lesions.18 Lesions in persons with less effective immune systems progress to primary progressive tuberculosis.4,8,13,18

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Figure 1 Pathophysiology of tuberculosis: inhalation of bacilli (A), containment in a granuloma (B), and breakdown of the granuloma in less immunocompetent individuals (C). For less immunocompetent persons, granuloma formation is initiated yet ultimately is unsuccessful in containing the bacilli. The necrotic tissue undergoes liquefaction, and the fibrous wall loses structural integrity. The semiliquid necrotic material can then drain into a bronchus or nearby blood vessel, leaving an air-filled cavity at the original site. In patients infected with M tuberculosis,droplets can be coughed up from the bronchus and infect other persons. If discharge into a vessel occurs, occurrence of extrapulmonary tuberculosis is likely. Bacilli can also drain into the lymphatic system and collect in the tracheobronchial lymph nodes of the affected lung, where the organisms can form new caseous granulomas.18 Previous SectionNext Section

Clinical Manifestations
As the cellular processes occur, tuberculosis may develop differently in each patient, according to the status of the patients immune system. Stages include latency, primary disease, primary progressive disease, and extrapulmonary disease. Each stage has different clinical manifestations (Table 1).
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Table 1 Differences in the stages of tuberculosis

Latent Tuberculosis Mycobacterium tuberculosis organisms can be enclosed, as previously described, but are difficult to completely eliminate.15 Persons with latent tuberculosis have no signs or symptoms of the disease, do not feel sick, and are not infectious.19However, viable bacilli can persist in the necrotic material for years or even a lifetime, 9 and if the immune system later becomes compromised, as it does in many critically ill patients, the disease can be reactivated. Although coinfection with human immunodeficiency virus is the most notable cause for progression to active disease, other factors, such as uncontrolled diabetes mellitus, sepsis, renal failure, malnutrition, smoking, chemotherapy, organ transplantation, and long-term corticosteroid usage, that can trigger reactivation of a remote infection are more common in the critical care setting. 8,19 Additionally, persons 65 years or older have a disproportionately higher rate of disease than any does other age group, 20 often because of diminishing immunity and reactivation of disease.21 Primary Disease Primary pulmonary tuberculosis is often asymptomatic, so that the results of diagnostic tests (Table 2) are the only evidence of the disease. Although primary disease essentially exists subclinically, some self-limiting findings might be noticed in an assessment. Associated paratracheal lymphadenopathy may occur because the bacilli spread from the lungs through the lymphatic system. If the primary lesion enlarges, pleural effusion is a distinguishing finding. This effusion develops because the bacilli infiltrate the pleural space from an adjacent area. The effusion may remain small and resolve spontaneously, or it may become large enough to induce symptoms such as fever, pleuritic chest pain, and dyspnea. Dyspnea is due to poor gas exchange in the areas of affected lung tissue. Dullness to percussion and a lack of breath sounds are physical findings indicative of a pleural effusion because excess fluid has entered the pleural space.7
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Table 2 Diagnostic tests for identifying tuberculosis Primary Progressive Tuberculosis Active tuberculosis develops in only 5% to 10% of persons exposed to M tuberculosis. When a patient progresses to active tuberculosis, early signs and symptoms are often nonspecific. Manifestations often include progressive fatigue, malaise, weight loss, and a low-grade fever accompanied by chills and night sweats. 22 Wasting, a classic feature of tuberculosis, is due to the lack of appetite and the altered metabolism associated with the inflammatory and immune responses. Wasting involves the loss of both fat and lean tissue; the decreased muscle mass contributes to the fatigue.23 Finger clubbing, a late sign of poor oxygenation, may occur; however, it does not indicate the extent of disease.24 A cough eventually develops in most patients. Although the cough may initially be nonproductive, it advances to a productive cough of purulent sputum. The sputum may also be streaked with blood. Hemoptysis can be due to destruction of a patent vessel located in the wall of the cavity, the rupture of a dilated vessel in a cavity, or the formation of an aspergilloma in an old cavity. The inflamed parenchyma may cause pleuritic chest pain. Extensive disease may lead to dyspnea or orthopnea because the increased interstitial volume leads to a decrease in lung diffusion capacity. Although many patients with active disease have few physical findings, rales may be detected over involved areas during inspiration, particularly after a cough. Hematologic studies might reveal anemia, which is the cause of the weakness and fatigue. Leukocytosis may also occur because of the large increase in the number of leukocytes, or white blood cells, in response to the infection. 7 Extrapulmonary Tuberculosis Although the pulmonary system is the most common location for tuberculosis, extrapulmonary disease occurs in more than 20% of immunocompetent patients, and the risk for extrapulmonary disease increases with immunosuppression.20The most serious location is the central nervous system, where infection may result in meningitis or space-occupying tuberculomas. If not treated, tubercular meningitis is fatal in most cases, making rapid detection of the mycobacteria essential.8 Headaches and change in mental status after possible exposure to

tuberculosis or in high risk groups should prompt consideration of this disease as a differential diagnosis. Another fatal form of extrapulmonary tuberculosis is infection of the bloodstream by mycobacteria; this form of the disease is called disseminated or miliary tuberculosis. The bacilli can then spread throughout the body, leading to multiorgan involvement.25 Miliary tuberculosis progresses rapidly and can be difficult to diagnose because of its systemic and nonspecific signs and symptoms, such as fever, weight loss, and weakness. 7 Lymphatic tuberculosis is the most common extrapulmonary tuberculosis, and cervical adenopathy occurs most often. Other possible locations include bones, joints, pleura, and genitourinary system. 20 Previous SectionNext Section

Laboratory and Diagnostic Studies

Active tuberculosis may be considered as a possible diagnosis when findings on a chest radiograph of a patient being evaluated for respiratory symptoms are abnormal, as occurs in most patients with pulmonary tuberculosis. The radiographs may show the characteristic findings of infiltrates with cavitation in the upper and middle lobes of the lungs21 (Figure 2). However, specific groups of patients, such as the elderly and patients with advanced infection by human immunodeficiency virus, may not have these typical findings. Compared with other patients, both groups have the classic cavitation less often and may have lower-lobe infiltrates as a prominent finding.7,21 Although abnormal findings on a chest radiograph may suggest tuberculosis, they are not diagnostic for the disease. 19

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Figure 2 Chest radiographs in pulmonary tuberculosis. A, Infiltrates in left lung. B, Bilateral advanced pulmonary tuberculosis and cavitation in apical area of right lung. Traditionally, the first laboratory test used to detect active tuberculosis in a patient with abnormal findings on chest radiographs is examination of a sputum smear for the presence of acid-fast bacilli (Table 2). Also, because the bacilli have entered the sputum, the patient is infectious to others. According to the Centers for Disease Control and Prevention,19 3 sputum specimens should be used for detection of pulmonary tuberculosis, with specimens collected in the morning on consecutive days. However, recently, investigators have questioned the need for 3 specimens. Leonard et al27 concluded that examination of 2 specimens is just as sensitive. For the test, sputum is smeared on a slide, stained, dried, and then treated with alcohol. Any bacilli that are present will remain red because they will not destain. The test is not specific for tuberculosis, because other mycobacteria give the same results, but it does provide a quick method to determine if respiratory precautions should be maintained while more definitive testing is performed. Results of sputum smears should be available within 24 hours of the specimen collection.19 Previous SectionNext Section

Diagnosis
The Standard Definitive diagnosis of tuberculosis requires the identification of M tuberculosisin a culture of a diagnostic specimen. The most frequent sample used from a patient with a persistent and productive cough is sputum. Because most mycobacteria grow slowly, 3 to 6 weeks may be required for detectable growth on solid media. However, a newer, alternative method in which high-performance liquid chromatography is used to isolate and differentiate cell

wall mycolic acids provides confirmation of the disease in 4 to 14 days. 19 Conventionally, 3 sputum samples were also used for culture diagnosis, but the use of 2 specimens, as mentioned earlier for smears, also applies for cultures.27 After medications are started, the effectiveness of the therapy is assessed by obtaining sputum samples for smears. Once again, the traditional requirement of 3 sputum smears negative for M tuberculosis may be unnecessary when determining if respiratory isolation can be discontinued.28 A patient is considered to have achieved culture conversion when a culture is negative for the mycobacteria after a succession of cultures have been positive; culture conversion is the most important objective evaluation of response to treatment. 19 Alternatives Unfortunately, not all patients with tuberculosis can be detected by culture of sputum specimens, a situation that can lead to delayed or missed diagnosis.20,29Additionally, many critically ill patients have trouble producing the necessary material from the lungs and instead produce saliva or nasopharyngeal discharge. For patients who have difficulty generating sputum, inhalation of an aerosol of normal saline can be used to induce sputum for collection.4,7,19 However, if sputum specimens are still inadequate, or the index of suspicion for tuberculosis is still high despite cultures negative for M tuberculosis, alternative approaches are available. Bronchoscopy with bronchial washings or bronchoalveolar lavage can provide sputum for diagnosis.19 In bronchial washing, a fiberoptic bronchoscope is inserted into the lungs, and fluid is squirted in and then collected, essentially washing out a sample of cells and secretions from the alveolar and bronchial airspaces. Aliquots obtained from subsequent lavages constitute bronchoalveolar lavage specimens.30 In patients with involvement of intrathoracic lymph nodes, as indicated by adenopathy suggestive of tuberculosis, who have sputum smears negative for M tuberculosis, culture of specimens collected by transbronchial needle aspiration can be used to accurately and immediately diagnose the disease. With this technique, specimens are collected by inserting a 19-gauge flexible histology needle through a bronchoscopy tube; patients are sedated but conscious, and computed tomography scans are used for guidance. 31 Technological Advancements Newer diagnostic techniques for faster detection of M tuberculosis include nucleic acid amplification tests. In these tests, molecular biology methods are used to amplify DNA and RNA, facilitating rapid detection of microorganisms; the tests have been approved by the Food and Drug Administration. 32 One method is the polymerase chain reaction assay, which can be used to differentiate M tuberculosis from other mycobacteria on the basis of genetic information and provides results within hours. Although the test can provide rapid confirmation ofM tuberculosis in sputum specimens positive for acid-fast bacilli, it has limitations, including high cost, low sensitivity, and low availability. A polymerase chain reaction assay positive for M tuberculosis in conjunction with a sputum smear positive for the organism indicates true tuberculosis, but in a patient with a sputum smear negative for the organism, the positive polymerase chain reaction assay should be considered carefully along with clinical indicators. The results of these assays can not be relied on as the sole guide for isolation or therapy.33 Previous SectionNext Section

Diagnosing Latency
Once patients recover from a primary M tuberculosis infection and the infection becomes latent, sputum specimens are negative for the organisms, and findings on chest radiographs are typically normal. These patients also do not have signs or symptoms of infection, and they are not infectious to others. Tuberculin skin testing is the most common method used to screen for latent M tuberculosis.3 The tuberculin skin test is performed by intradermally injecting 0.1 mL of intermediate-strength purified protein derivative (PPD) that contains 5 tuberculin units. After 48 to 72 hours, the injection site is examined for induration but not redness (Figure 3, Table 3). Although the test is useful because the PPD elicits a skin reaction via cellmediated immunity when injected in patients previously infected with mycobacteria, it is limited because it is not specific for the species of mycobacteria. Many proteins in the PPD product are highly conserved in various species of mycobacteria. Also, the test is of limited value in patients with active tuberculosis because of its low sensitivity and specificity. False-negatives can occur in patients who are immunocompromised or malnourished, because these patients cannot mount an immune response to the injection, and in 20% to 25% of patients who have active tuberculosis, because there is a time lag of 2 to 10 weeks between infection and the T-lymphocyte response required for a positive skin reaction. False-positives can occur in patients who have infections caused by mycobacteria other than M tuberculosis or who have been given BCG vaccine.35

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Table 3 Positive tuberculin skin tests

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Figure 3 Measuring induration, not erythema, in a tuberculin skin test. The tuberculin skin test was the only test available to detect latent tuberculosis until an interferon-release assay, called QuantiFERON-TB test, was approved by the Food and Drug Administration in 2001. Then, in 2005, a new interferon-assay, called QuantiFERON-TB Gold was approved and is intended to replace the QuantiFERON-TB test, which is no longer commercially available. In both tests, the cell-mediated reactivity to M tuberculosis is determined by incubating whole blood with an antigen and then using an enzyme-linked immunosorbent assay to measure the amount of interferon- released from white blood cells. In the QuantiFERON-TB Gold test, 2 synthetic antigenic proteins specific in PPD are used rather than a PPD admixture, making this test more sensitive than its predecessor. QuantiFERON-TB Gold provides results in less than 24 hours and can be used to detect both active and latent tuberculosis. The results of the QuantiFERON-TB Gold test are similar to those of the tuberculin skin test, and the Centers for Disease Control and Prevention now recommend that the QuantiFERON-TB Gold test be used in all instances in which the tuberculin skin test formerly would have been used. 32 Previous SectionNext Section

Implications for Critical Care Nurses

With the reemergence of tuberculosis, being well informed about this disease is more important than before. Tuberculosis can be difficult to diagnose promptly, resulting in delayed isolation of patients and potential spread of the disease. Detection of extrapulmonary tuberculosis is generally even more difficult because this type is often less familiar to clinicians.7 Nurses play an important role in recognizing the clinical signs and symptoms of tuberculosis, a situation that places them in a position for early recognition of the disease, leading to diagnosis and early isolation to prevent transmission. Importantly, diagnosis may be based on clinical manifestations even without a culture positive for M tuberculosis.19 Nurses are also in a position to optimize nutrition, educate, provide emotional support, and prepare patients and patients families for discharge from the hospital. Nearly every type of health care setting has been implicated in the transmission of M tuberculosis.9 The emergency department can play a vital role in control because it is a point of entry into the hospital. However, because of the nonspecific signs and symptoms and dated screening protocols, initial detection of tuberculosis is still missed in

emergency department triage. 36 Consequently, a patient with tuberculosis can be discharged into the community or admitted to the hospital without any intervention. Patients admitted because of trauma may also escape screening for tuberculosis, because the focus is almost entirely on injuries. Often trauma patients are admitted to an intensive care unit, where other patients are particularly susceptible to any infection. Intubated patients are compromised directly from the pulmonary standpoint and lack normal upper airway defenses that protect the lungs from bacteria. Many nosocomial tuberculosis outbreaks have been reported,36 emphasizing that nurses and other health care personnel should remember that even hospitalized patients may have tuberculosis. Isolation Because nurses play a key role in detecting tuberculosis, they should advocate for prompt isolation of patients with suspected or confirmed M tuberculosis infection (Figure 4). Nurses should be familiar with the isolation precautions that must be implemented. Patients with suspected tuberculosis should be placed in a negative-pressure room, and appropriate particulate respiratory masks (N-95/high-efficiency particulate air filters) should be readily available outside the door for anyone entering the room. 37 The number of visitors should be minimized, and children should be discouraged from visiting. Patients should be instructed to cover their nose and mouth with a tissue when sneezing or coughing. Additionally, they should wear a mask when leaving the room, and nonurgent procedures should be postponed until the infectious phase has passed.
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Figure 4 A general plan-of-care algorithm for a patient who may have tuberculosis. Patients receiving mechanical ventilation should also be kept in a negative-pressure room, and respiratory masks should still be used by anyone who enters the room. A closed-system endotracheal suction catheter should be used for suctioning whenever feasible. In order to help reduce the risk of contaminating ventilation equipment or release of M tuberculosis organisms into the room air, a bacterial filter should be placed on the endotracheal tube or on the expiratory side of the ventilation circuit. Good oral care and strict adherence to suctioning infection control practices should be a priority, because ventilator-associated pneumonia is already a predominant nosocomial infection and would pose an enhanced threat to a patient with tuberculosis. Nutrition Adequate nutrition is an important feature though all stages of infection. Malnutrition appears to increase the risk for tuberculosis; persons with low body mass index are greatly more at risk for tuberculosis than are those with a high index.38 Additionally, among patients underweight at the time of diagnosis, those who increase their weight by 5% during the first 2 months of treatment have significantly less relapse than do patients who gain less than 5%.38 Nurses should take particular note of underweight tuberculosis patients, recognizing that being underweight is a risk factor for relapse and encouraging aggressive nutritional support.39 Also, because functional recovery often lags behind microbiological cure, the aim of nutritional intervention should be to restore lean tissue.23,39 Nurses should also encourage patients to engage in physical activity to counter the loss of muscle mass and subsequent fatigue. Advocating for a nutritionist and physical therapist to evaluate a patient with tuberculosis to make patientspecific recommendations would be an appropriate action for nurses. Emotional Support and Education In addition to the direct responsibilities of nursing, many nurses are also a key source of emotional support for patients and patients families during times of illness. Perceived emotional support from nursing staff can improve adherence to therapy. Many patients with tuberculosis experience feelings of guilt and face stigma, and patients family members often fear associating with the patients.40Nurses can provide education to patients and patients families about transmission and treatment to help reduce misconceptions and can elicit conversations to communicate concerns. Encouragement combined with education can affect a patients adherence to therapy, as well as improve the patients mood and perception of the illness. Previous SectionNext Section

Conclusions
Tuberculosis has reemerged as a major public health concern and is the second deadliest infectious disease worldwide. Understanding the pathophysiology of this contagious airborne disease, from the primary infection to primary progressive (active) disease or latency, is important. Understanding the pathophysiology will help critical care nurses be aware of the causes of the classic signs and symptoms for tuberculosis. Many different diagnostic tests can be used to evaluate a patient with suspected tuberculosis, and the stage or progression of the disease markedly affects the results. Even in critical care, each nurse has an opportunity to contribute to the control of tuberculosis by learning about the signs and symptoms of the disease, risk factors specific to critical care patients, and the appropriate actions to take should such a case occur. The more nurses know about tuberculosis, the more they can contribute to minimizing its transmission, making early diagnoses, and preventing increases in morbidity and mortality due to this disease. Previous SectionNext Section

PRIME POINTS
The vulnerability of hospitalized patients to tuberculosis is often underrecognized because the infection is habitually considered a disease of the community. Read the article to find out how to obtain a definitive diagnosis of tuberculosis. Learn about tuberculosis test like the QuantiFERON-TB Gold test and how it is being used. Nurses should advocate for prompt isolation of patients with suspected or confirmed tuberculosis.

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Footnotes

To purchase electronic or print reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 899-1712 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints@aacn.org. dotmore To read more about tuberculosis, read The Pursuit of Healthcare by Christopher W. Bryan-Brown and Kathleen Dracup in the American Journal of Critical Care, 2004;13: 368370. Available atwww.ajcconline.org.

What is pleural effusion?

A pleural effusion is a collection of fluid in the space between the two linings (pleura) of the lung. When we breathe, it is like a bellows. We inhale air into our lungs and the ribs move out and the diaphragm moves down. For the lung to expand, its lining has to slide along with the chest wall movement. For this to happen, both the lungs and the ribs are covered with a slippery lining called the pleura. A small amount of fluid acts as a lubricant for these two surfaces to slide easily against each other. Too much fluid impairs the ability of the lung to expand and move.

What causes pleural effusion?

A pleural effusion is not normal. It is not a disease but rather a complication of an underlying illness. Extra fluid (effusion) can occur for a variety of reasons. Common classification systems divide pleural effusions based on the chemistry composition of the fluid and what causes the effusion to be formed. Two classifications are 1) transudate pleural effusions; and 2) exudate pleural effusions. Sometimes the pleural effusion can have characteristics of both a transudate and an exudate. 1. Transudate pleural effusions are formed when fluid leaks from blood vessels into the pleural space. Chemically, transudate pleural effusions contain less protein and LDH (lactate dehydrogenase) than exudate pleural effusions. If both the pleural fluidtoserum total protein ratio is less than or equal to 0.50 and the pleural fluidtoserum LDH ratios are less than or equal to 0.67, the fluid is usually considered to be a transudate while exudates ratios are above 0.50 and above 0.67. Examples of transudate pleural effusions include:

congestive heart failure,

liver failure or cirrhosis, kidney failure or nephritic syndrome, and peritoneal dialysis.

2. Exudate pleural effusions are caused by inflammation of the pleura itself and are often due to disease of the lung. Examples of exudate causes include:

lung or breast cancer, lymphoma, pneumonia, tuberculosis, post pericardotomy syndrome, systemic lupus erythematosus, uremia or kidney failure, Meigs syndrome, pancreatic pseudocyst, ascites, intra abdominal abscess, and asbestosis and mesothelioma.

Most pleural effusions are caused by congestive heart failure, pneumonia, pulmonary embolism and malignancy.

What are the risk factors for pleural effusion?

Since a pleural effusion is a manifestation of another illness, the risk factors are those of the underlying disease. In general, pleural effusions are seen in adults and less commonly in children.

What are the symptoms and signs of pleural effusion?

Shortness of breath is the most common symptom of a pleural effusion. As the effusion grows larger with more fluid, the harder it is for the lung to expand and the more difficult it is for the patient to breathe. Chest pain occurs because the pleural lining of the lung is irritated. The pain is usually described as pleuritic, defined as a sharp pain, worsening with a deep breath. While the pain may be localized to the chest, if the effusion causes inflammation of the diaphragm (the muscle that divides the chest from the abdominal cavity) the pain may be referred to the shoulder or the upper abdomen. As the pleural effusion increases in size, the pain may increase. Other associated symptoms are due to the underlying disease. For example, individuals with:

congestive heart failure may complain of swelling of their feet and shortness of breath when laying flat, (orthopnea) or wakening them in the middle of the night (paroxysmal nocturnal dyspnea); tuberculosis may be have night sweats, cough up blood (hemoptysis), and loose weight; hemoptysis may have associated infection and lung cancer; pneumonia may complain of fever, shaking chills, cough producing colored sputum and pleuritic pain.

Pleural Effusion Risks

Factors that increase your chance of getting pleural effusion include: o o o o o o Pneumonia, tuberculosis, or other lung diseases Heart Attack , heart failure, or infections such asPericarditis , recent cardiac surgery Pleurisy Liver disease Tumors Pregnancy, recent delivery Connective tissue diseases, such as Rheumatoid Arthritisand Systemic Lupus Erythematosus Certain medications: Nitrofurantoin (Macrodantin, Furadantin, Macrobid) Dantrolene (Dantrium) Methysergide (Sansert) Bromocriptine (Parlodel) Procarbazine (Matulane) Amiodarone (Cordarone) Cancers, such as lung, breast, lymphoma, or Pleural Mesothelioma Chest injury or trauma Radiation therapy Pulmonary Embolism (blood clot in the lungs) Abdominal infections or Pancreatitis

 o o o o

Surgery, especially involving Heart Lungs Abdomen Organ transplantation

tuberculosis (TB), infectious disease that is caused by the tubercle bacillus,Mycobacterium tuberculosis. In most forms of the disease, the bacillus spreads slowly and widely in the lungs, causing the formation of hard nodules (tubercles) or large cheeselike masses that break down the respiratory tissues and form cavities in the lungs. Blood vessels also can be eroded by the advancing disease, causing the infected person to cough up bright red blood. During the 18th and 19th centuries, tuberculosis reached near-epidemic proportions in the rapidly urbanizing and industrializing societies of Europe and North America. Indeed, consumption, as it was then known, was the leading cause of death for all age groups in the Western world from that period until the early 20th century, at which time improved health and hygiene brought about a steady decline in its mortality rates. Since the 1940s, antibiotic drugs have reduced the span of treatment to months instead of years, and drug therapy has done away with the old TB sanatoriums where patients at one time were nursed for years while the defensive properties of their bodies dealt with the disease. Today, in less-developed countries where population is dense and hygienic standards poor, tuberculosis remains a major fatal disease. The prevalence of the disease has increased in association with the HIV/AIDS epidemic; an estimated one out of every four deaths from tuberculosis involves an individual coinfected with HIV. In addition, the successful elimination of tuberculosis as a major threat to public health in the world has been complicated by the rise of new strains of the tubercle bacillus that are resistant to conventional antibiotics. Infections with these strains are often difficult to treat and require the use of combination drug therapies, sometimes involving the use of five different agents.

The course of tuberculosis

Table Of Contents

The tubercle bacillus is a small, rod-shaped bacterium that is extremely hardy; it can survive for months in a state of dryness and can also resist the action of mild disinfectants. Infection spreads primarily by the respiratory route directly from an infected person who discharges live bacilli into the air. Minute droplets ejected by sneezing, coughing, and even talking can contain hundreds of tubercle bacilli that may be inhaled by a healthy person. There the bacilli become trapped in the tissues of the body, are surrounded by immune cells, and finally are sealed up in hard, nodular tubercles. A tubercle usually consists of a centre of dead cells and tissues, cheeselike (caseous) in appearance, in which can be found many bacilli. This centre is surrounded by radially arranged phagocytic (scavenger) cells and a periphery containing

connective tissue cells. The tubercle thus forms as a result of the bodys defensive reaction to the bacilli. Individual tubercles are microscopic in size, but most of the visible manifestations of tuberculosis, from barely visible nodules to large tuberculous masses, are conglomerations of tubercles. In otherwise healthy children and adults, the primary infection often heals without causing symptoms. The bacilli are quickly sequestered in the tissues, and the infected person acquires a lifelong immunity to the disease. A skin test taken at any later time may reveal the earlier infection and the immunity, and a small scar in the lung may be visible by X-ray. In this condition, sometimes called latent tuberculosis, the affected person is not contagious. In some cases, however, sometimes after periods of time that can reach 40 years or more, the original tubercles break down, releasing viable bacilli into the bloodstream. From the blood the bacilli create new tissue infections elsewhere in the body, most commonly in the upper portion of one or both lungs. This causes a condition known as pulmonary tuberculosis, a highly infectious stage of the disease. In some cases the infection may break into the pleural space between the lung and the chest wall, causing a pleural effusion, or collection of fluid outside the lung. Particularly among infants, the elderly, and immunocompromised adults (organ transplant recipients or AIDS patients, for example), the primary infection may spread through the body, causing miliary tuberculosis, a highly fatal form if not adequately treated. In fact, once the bacilli enter the bloodstream, they can travel to almost any organ of the body, including the lymph nodes, bones and joints, skin, intestines, genital organs, kidneys, and bladder. An infection of the meninges that cover the brain causes tuberculous meningitis; before the advent of specific drugs, this disease was always fatal, though most affected people now recover. The onset of pulmonary tuberculosis is usually insidious, with lack of energy, weight loss, and persistent cough. These symptoms do not subside, and the general health of the patient deteriorates. Eventually, the cough increases, the patient may have chest pain from pleurisy, and there may be blood in the sputum, an alarming symptom. Fever develops, usually with drenching night sweats. In the lung, the lesion consists of a collection of dead cells in which tubercle bacilli may be seen. This lesion may erode a neighbouring bronchus or blood vessel, causing the patient to cough up blood (hemoptysis). Tubercular lesions may spread extensively in the lung, causing large areas of destruction, cavities, and scarring. The amount of lung tissue available for the exchange of gases in respiration decreases, and if untreated the patient will die from failure of ventilation and general toxemia and exhaustion.
The diagnosis of pulmonary tuberculosis depends on finding tubercle bacilli in the sputum, in the urine, in gastric washings, or in the cerebrospinal fluid. The primary method used to confirm the presence of bacilli is a sputum smear, in which a sputum specimen is smeared onto a slide, stained with a compound that penetrates the organisms cell wall, and examined under a microscope. If bacilli are present, the sputum specimen is cultured on a special medium to determine whether the bacilli are M. tuberculosis. An X-ray of the lungs may show typical shadows caused by tubercular nodules or lesions. The prevention of tuberculosis depends on good hygienic and nutritional conditions and on the identification of infected patients and their early treatment. A vaccine, known as BCG vaccine, is composed of specially weakened tubercle bacilli. Injected into the skin, it causes a local reaction, which confers some immunity to infection by M. tuberculosis for several years. It has been widely used in some countries with success; its use in young children in particular has helped to

control infection in the developing world. The main hope of ultimate control, however, lies in preventing exposure to infection, and this means treating infectious patients quickly, possibly in isolation until they are noninfectious. In many developed countries, individuals at risk for tuberculosis, such as health care workers, are regularly given a skin test (see tuberculin test) to show whether they have had a primary infection with the bacillus. Today, the treatment of tuberculosis consists of drug therapy and methods to prevent the spread of infectious bacilli. Historically, treatment of tuberculosis consisted of long periods, often years, of bed rest and surgical removal of useless lung tissue. In the 1940s and 50s several antimicrobial drugswere discovered that revolutionized the treatment of patients with tuberculosis. As a result, with early drug treatment, surgery is rarely needed. The most commonly used antituberculosis drugs areisoniazid and rifampicin (rifampin). These drugs are often used in various combinations with other agents, such as ethambutol, pyrazinamide, or rifapentine, in order to avoid the development of drug-resistant bacilli. Patients with strongly suspected or confirmed tuberculosis undergo an initial treatment period that lasts two months and consists of combination therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide. These drugs may be given daily or two times per week. The patient is usually made noninfectious quite quickly, but complete cure requires continuous treatment for another four to nine months. The length of the continuous treatment period depends on the results of chest X-rays and sputum smears taken at the end of the two-month period of initial therapy. Continuous treatment may consist of once daily or twice weekly doses of isoniazid and rifampicin or isoniazid and rifapentine. If a patient does not continue treatment for the required time or is treated with only one drug, bacilli will become resistant and multiply, making the patient sick again. If subsequent treatment is also incomplete, the surviving bacilli will become resistant to several drugs. Multidrug-resistant tuberculosis (MDR TB) is a form of the disease in which bacilli have become resistant to isoniazid and rifampicin. MDR TB is treatable but is extremely difficult to cure, typically requiring two years of treatment with agents known to have more severe side effects than isoniazid or rifampicin. Extensively drug-resistant tuberculosis (XDR TB) is a rare form of MDR TB. XDR TB is characterized by resistance to not only isoniazid and rifampin but also a group of bactericidal drugs known as fluoroquinolones and at least one aminoglycoside antibiotic, such as kanamycin, amikacin, or capreomycin. Aggressive treatment using five different drugs, which are selected based on the drug sensitivity of the specific strain of bacilli in a patient, has been shown to be effective in reducing mortality in roughly 50 percent of XDR TB patients. In addition, aggressive treatment can help prevent the spread of strains of XDR TB bacilli. In 1995, in part to prevent the development and spread of MDR TB, the World Health Organization began encouraging countries to implement a compliance program called directly observed therapy(DOT). Instead of taking daily medication on their own, patients are directly observed by a clinician or responsible family member while taking larger doses twice a week. Although some patients consider DOT invasive, it has proved successful in controlling tuberculosis.

Despite stringent control efforts, however, drug-resistant tuberculosis remained a serious threat in the early 21st century. In 2009, for example, researchers reported the emergence of extremely drugresistant tuberculosis (XXDR-TB), also known as totally drug-resistant tuberculosis (TDR-TB), in a small subset of Iranian patients. This form of the disease, which had also been detected in Italy (in 2003) and India (in 2011), is resistant to all first- and second-line antituberculosis drugs.