DEFINITION (W)
Tuberculosis is a common infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis.Tuberculosis most commonly attacks the lungs but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, bones, joints and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti can also cause tuberculosis, but these species do not usually infect healthy adults.
h3. EPIDEMIOLOGY
According to the World Health Organization (WHO), nearly 2 billion people—one–third of the world's population—have been exposed to the tuberculosis pathogen. Annually, 8 million people become ill with tuberculosis, and 2 million people die from the disease worldwide. In 2004, around 14.6 million people had active TB disease with 9 million new cases. The annual incidence rate varies from 356 per 100,000 in Africa to 41 per 100,000 in the Americas. Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS.
In 2004, the country with the highest incidence of TB was South Africa, with 718 cases per 100,000 people. India has the largest number of infections, with over 1.8 million cases. In developed countries, tuberculosis is less common and is mainly an urban disease. In the United Kingdom, TB incidences range from 40 per 100,000 in London to less than 5 per 100,000 in the rural South West of England; the national average is 13 per 100,000. The highest rates in Western Europe are in Portugal (42 per 100,000) and Spain (20 per 100,000). These rates compare with 113 per 100,000 in China and 64 per 100,000 in Brazil. In the United States, the overall tuberculosis case rate was 4.9 per 100,000 persons in 2004.
The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults. However, in countries where TB has gone from high to low incidence, such as America, TB is mainly a disease of older people.
There are a number of known factors that make people more susceptible to TB infection: worldwide the most important of these is HIV. Co-infection with HIV is a particular problem in Sub-Saharan Africa, due to the high incidence of HIV in these countries. Smoking more than 20 cigarettes a day also increases the risk of TB by two- to four-times. Diabetes mellitus is also an important risk factor that is growing in importance in developing countries.
SYMPTOMS
When the disease becomes active, 75% of the cases are pulmonary TB. Symptoms include chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to fatigue very easily.
In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB more common in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura, the central nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Although extrapulmonary TB is not contagious, it may co-exist with pulmonary TB, which is contagious.
The current clinical classification system for tuberculosis is based on the pathogenesis of the disease.
Health care providers should comply with local laws and regulations requiring the reporting of TB. All persons with class 3 or class 5 TB should be reported promptly to the local health department.
DIAGNOSIS
Tuberculosis can be a difficult disease to diagnose, due mainly to the difficulty in culturing this slow-growing organism in the laboratory. A complete medical evaluation for TB must include a medical history, a chest X-ray, and a physical examination. Tuberculosis radiology is used in the diagnosis of TB. It may also include a tuberculin skin test, a serological test, microbiological smears and cultures. The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression.
Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to purified protein derivatives of M. tuberculosis. Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection and thus the test must be used with caution, particularly with regard to persons from countries where TB immunization is common. New TB tests are being developed that offer the hope of cheap, fast and more accurate TB testing. These use polymerase chain reaction detection of bacterial DNA and antibody assays to detect the release of interferon gamma in response to mycobacteria. Rapid and inexpensive diagnosis will be particularly valuable in the developing world.
Research for practice: a new in vitro test for identification of tuberculosis infection
Operational feasibility of using loop-mediated isothermal amplification for diagnosis of pulmonary tuberculosis in microscopy centers of developing countries
PATHOGENESIS
About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease. However, if untreated, the death rate for these active TB cases is more than 50%.
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within alveolar macrophages. The primary site of infection in the lungs is called the Ghon focus. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to the more distant tissues and organs where secondary TB lesions can develop in lung apices, peripheral lymph nodes, kidneys, brain, and bone. All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.
Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes (CD4+) secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected. T lymphocytes (CD8+) can also directly kill infected cells.
Importantly, bacteria are not always eliminated within the granuloma, but can become dormant, resulting in a latent infection. 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 bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. Patients with this disseminated TB have a fatality rate of approximately 20%, even with intensive treatment.
In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.
PREVENTION
TB prevention and control takes two parallel approaches. In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB. Unfortunately, no vaccine is available that provides reliable protection for adults. However, in tropical areas where the incidence of atypical mycobacteria is high, exposure to nontuberculous mycobacteria gives some protection against TB.
Many countries use BCG vaccine as part of their TB control programs, especially for infants. This was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921. However, mass vaccination with BCG did not start until after World War II.The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.
In South Africa, the country with the highest prevalence of TB, BCG is given to all children under the age of three. However, the effectiveness of BCG is lower in areas where mycobacteria are less prevalent, therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:
* Infants or children with negative skin-test result who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
* Healthcare workers considered on an individual basis in settings in which 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.
Several new vaccines to prevent TB infection are being developed. 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). A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans. A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University, and is based on a genetically modified vaccinia virus. 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.
TREATMENT
Treatment for TB uses antibiotics to kill the bacteria. The two antibiotics most commonly used are rifampicin and isoniazid. However, instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 12 months) to entirely eliminate mycobacteria from the body. Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance. People with these latent infections are treated to prevent them from progressing to active TB disease later in life. However, treatment using Rifampin and Pyrazinamide is not risk-free. The Centers for Disease Control and Prevention (CDC) notified healthcare professionals of revised recommendations against the use of rifampin plus pyrazinamide for treatment of latent tuberculosis infection, due to high rates of hospitalization and death from liver injury associated with the combined use of these drugs.
Drug resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance occurs in persons who are infected with a resistant strain of TB. A patient with fully-susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low quality medication. Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug resistant 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.
Current Anti-TB Chemotherapy
The current standard chemotherapeutic regimen for active TB—directly observed therapy, short course (DOTS)—requires the supervised administration of a multidrug combination for a minimum period of 6 months. The frontline drugs are biased towards interference in cell wall integrity, with the actively dividing M. tuberculosis population in the lung cavity, which is key to transmission and emergence of drug resistance, being the principal target. M. tuberculosis replication in pulmonary cavities most closely resembles optimal aerobic growth in vitro, and the effectiveness of the frontline drugs in treating acute TB is manifest in rapid bacillary clearance within the first 2 months of chemotherapy. Differences in drug susceptibilities between replicating and nondividing bacterial cells can be significant, however, and the dependence of the frontline anti-TB drugs on actively replicating cells for activity is probably the greatest limitation of current therapy . This weakness is further reflected in the profound disparity between in vitro and in vivo efficacies of the majority of the frontline drugs, an additional factor dictating the complexity and duration of the DOTS regimen.
Poor antibiotic penetration, heterogeneity of host environments, and altered bacterial physiology and metabolic activity within those environments have all been blamed for impaired drug efficacies in vivo. However, the influence of the in vivo environment on drug efficacy should not be viewed as inevitably negative: pyrazinamide (PZA), for example, is inactive in vitro under standard culture conditions but displays strong sterilizing activity in vivo. Moreover, the activity of PZA in vivo correlates with enhanced in vitro activity under low pH and limiting oxygen, suggesting the relevance of these factors to the in vivo environment (discussed below). The absolute dependence on environmental factors for PZA activity has profound implications for the discovery of new anti-TB drugs, since it would almost certainly render this drug unidentifiable according to standard drug screening criteria, thereby eliminating a mainstay of current TB chemotherapy. At the very least, the differential effect of the in vivo environment on PZA versus the other frontline drugs emphasizes the need to understand the in vivo lifestyle of M. tuberculosis so that the factors influencing drug efficacy can be determined and new drug targets relevant to both latent and active disease can be identified.
PATIENT RISK FACTORS
Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease—1 to 5% of cases—this occurs soon after infection. However, in the majority of cases, a latent TB infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2 to 23% of these latent cases, often many years after infection. The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.
Other conditions that increase risk include drug injection, mainly due to the lifestyle of IV drug users; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; diabetes mellitus; silicosis; prolonged corticosteroid therapy and other immunosuppressive therapy; head and neck cancers; hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass or gastrectomy; chronic malabsorption syndromes; or low body weight.
An other risk factor is exposure to someone with TB. When people suffering from active pulmonary TB cough, sneeze, speak, kiss, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze, for instance, can release up to 40,000 droplets. People with prolonged, frequent, or intense contact are at highest risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year.
Twin studies in the 1950's showed that the course of TB infection was highly dependent on the genetics of the patient. At that time, it was rare that one identical twin would die and the other live.
Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.
CONDITIONS CONNECTED WITH TUBERCULOSIS INFECTION
Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence
Malnutrition in tuberculosis
Tuberculosis in patients treated with tumor necrosis factor-alpha antagonists living in an endemic area. Is the risk worthwhile?
Prognostic factors for pulmonary tuberculosis outcome in Recife, Pernambuco, Brazil
Genetic susceptibility to tuberculosis in Africans: A genome-wide scan
COMPLICATIONS
* Complications of lung infection:
o Progressive shortness of breath
o Pneumothorax
o Pleural effusion
Pulmonary TB can cause permanent lung damage when it's not diagnosed and treated early. Untreated active disease can also spread to other parts of the body where it can lead to serious or life-threatening complications. TB that infects the bone, for example, can cause severe pain, abscesses and joint destruction.
* Infection of TB spreading - to other body sites.
o Miliary tuberculosis - multiple abscesses in various body parts.
o Spine TB
o Meningitis
o Tuberculous meningitis
Tuberculosis meningitis occurs when TB infects your brain and central nervous system, and miliary TB, which occurs when TB bacteria spread throughout your entire body, are particularly dangerous forms of the disease. Children are especially susceptible to both meningeal TB and miliary TB.
o Kidney TB
o Kidney disease
o Peritonitis
o Pericarditis
o Lymph node infection
o Bone complications
o Joint complications
o Fallopian tube infection
o Bowel infection
o Recurrence - The most serious complication, however, is the recurrence of TB after the initial infection and the development of drug-resistant strains of the disease.
