1.

Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains ofmycobacteria, usually Mycobacterium tuberculosis. 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. Most infections areasymptomatic 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 thetuberculin 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 vaccination with the bacillus CalmetteGurin vaccine. One third of the world's population is thought to have been infected with M. tuberculosis, with new infections occurring at a rate of about one per second. In 2007, there were an estimated 13.7 million chronic active cases globally, while in 2010, there were an estimated 8.8 million new cases and 1.5 million associated deaths, mostly occurring in developing countries. The absolute number of tuberculosis cases has been decreasing since 2006, and new cases have decreased since 2002. 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. 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. Signs and symptoms The main symptoms of variants and stages of tuberculosis are given, 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. In contrast, 30% of those coinfected with HIV develop active disease. Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary tuberculosis). Extrapulmonary TB occurs when tuberculosis develops outside of the lungs. Extrapulmonary TB may coexist with pulmonary TB as well. General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue, and significant finger clubbing may also occur. Pulmonary If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases). Symptoms may include chest painand a prolonged cough producing sputum. About 25% of people may not have any symptoms (i.e. they remain "asymptomatic"). 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. The reason for this difference is not entirely clear. It may be due either to better air flow, or to poor lymph drainage within the upper lungs. Extrapulmonary In 1520% of active cases, the infection spreads outside the respiratory organs, causing other kinds of TB. These are collectively denoted as "extrapulmonary tuberculosis". Extrapulmonary TB occurs more commonly in immunosuppressed persons and young children. In those with HIV, this occurs in more than 50% of cases. 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), the genitourinary 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". a form of osteomyelitis. A potentially more serious, widespread form of TB is called "disseminated" TB, commonly known as miliary tuberculosis. Miliary TB makes up about 10% of extrapulmonary cases.
]

Causes Mycobacteria ( Mycobacterium tuberculosis) The main cause of TB is Mycobacterium tuberculosis, a small, aerobic, nonmotile bacillus. The high lipid content of this pathogen accounts for many of its unique clinical characteristics. 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. Mycobacteria have an outer membrane lipid bilayer. 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. MTB can withstand weak disinfectantsand 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. 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). 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, and theauramine-rhodamine stain followed by fluorescence microscopy. The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti. M. africanumis not widespread, but it is a significant cause of tuberculosis in parts of Africa. 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. M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants. M. microti is also rare and is mostly seen in immunodeficient people, although the prevalence of this pathogen has possibly been significantly underestimated. 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 norleprosy, but they do cause pulmonary diseases that resemble TB. 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] [29]

This is a particular problem insub-Saharan Africa, where rates of HIV are high.
[6]

[30][31]

Tuberculosis is closely

linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty.

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. with silicosis increasing the risk about 30-fold. nonsmokers.
[34] [33] [32]

Chronic lung disease is another significant risk factor -

Those who smoke cigarettes have nearly twice the risk of TB than
[6]

Other disease states can also increase the risk of developing tuberculosis, including alcoholism
[35]

and diabetes

mellitus (threefold increase).

Certain medications, such as corticosteroids and infliximab (an anti-TNF monoclonal antibody) are
[6]

becoming increasingly important risk factors, especially in the developed world. overall importance is still undefined. Mechanism
[6]

There is also a genetic susceptibility

[36]

for which

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 5.0 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
[38]

infectious dose of tuberculosis is very low (the inhalation of fewer than 10 bacteria may cause an infection).

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 1015 (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 virulenceof the M. tuberculosis strain, 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 nonresistant active infections generally do not remain contagious to others.
[39]

If someone does become infected, it

[41]

typically takes three to four weeks before the newly infected person becomes infectious enough to transmit the disease to others. Pathogenesis About 90% of those infected with M. tuberculosis have asymptomatic, latent TB infections (sometimes called LTBI), lifetime chance that the latent infection will progress to overt, active tuberculous disease. active TB increases to nearly 10% a year.
[43] [43] [42]

with only a 10%

In those with HIV, the risk of developing

[3]

If effective treatment is not given, the death rate for active TB cases is up to 66%.

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
[1]

part of the lower lobe, or the lower part of the upper lobe.

Tuberculosis of the lungs may also occur via infection from the blood
[45]

stream. This is known as a Simon focus and is typically found in the top of the lung.

This hematogenous transmission can also

[1][46]

spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones.

All parts of the body

[47]

can be affected by the disease, though for unknown reasons it rarely affects the heart, skeletal muscles, pancreas, or thyroid. Tuberculosis is classified as one of the granulomatous inflammatory diseases. Macrophages, T lymphocytes, B lymphocytes,

and fibroblasts are among the cells that aggregate to formgranulomas, 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 termed caseous 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. those with HIV, is called miliary tuberculosis. 30%).
[14][51] [50] [49]

This severe form of TB disease, most common in young children and

People with this disseminated TB have a high fatality rate even with treatment (about

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, areimmunosuppressed.
[53] [52]

as is diagnosing the disease in those who

A diagnosis of TB should, however, be considered in those with signs of lung disease or constitutional
[53]

symptoms lasting longer than two weeks. evaluation.

[53]

A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial
[54][55]

Interferon- release assays and tuberculin skin tests are of little use in the developing world.
[55][56]

IGRA have similar

limitations in those with HIV.

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. often begun before cultures are confirmed.
[58] [57]

Thus, treatment is

Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB. routinely recommended, as they rarely alter how a person is treated. they are not recommended. Latent tuberculosis
[59] [58]

[52]

These tests, however, are not

Blood tests to detect antibodies are not specific or sensitive, so

Mantoux tuberculin skin test The Mantoux tuberculin skin test is often used to screen people at high risk for TB. have a false-positive test result.
[60] [53]

Those who have been previously immunized may

The test may be falsely negative in those with sarcoidosis, Hodgkin's lymphoma, malnutrition, or
[1]

most notably, in those who truly do have active tuberculosis.

Interferon gamma release assays (IGRAs), on a blood sample, are These are not affected by immunization or most environmental

recommended in those who are positive to the Mantoux test. mycobacteria, so they generate fewer false-positive results. kansasii.
[62]

[58]

[61]

However they are affected by M. szulgai, M. marinum and M.

IGRAs may increase sensitivity when used in addition to the skin test but may be less sensitive than the skin test when
[63]

used alone. Prevention

Tuberculosis prevention and control efforts primarily rely on the vaccination of infants and the detection and appropriate treatment of active cases.
[6]

TheWorld Health Organization has achieved some success with improved treatment regimens, and a small decrease in
[6]

case numbers.

Leprosy, also known as Hansen's disease (HD), is a chronic disease caused by the bacteria Mycobacterium [1][2] leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosaof the upper respiratory tract; skin lesions are the primary [3] external sign. Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs and eyes. Contrary to folklore, leprosy does not cause body parts to fall off, although they can become numb or diseased as a result of secondary infections; these occur as a result of the body's defenses being compromised by the primary [4][5] disease. Secondary infections, in turn, can result in tissue loss causing fingers and toes to become shortened and [4][5][6] deformed, as cartilage is absorbed into the body. Although the mode of transmission of Hansen's disease remains uncertain, most investigators think that M. leprae is [7] usually spread from person to person in respiratory droplets. Studies have shown that leprosy can be transmitted to [8][9][10] humans by armadillos. Leprosy is now known to be neither sexually transmitted nor highly infectious after treatment. Approximately 95% of people are naturally immune and sufferers are no longer infectious after as little as 2 weeks of [11] treatment. The minimum incubation period reported is as short as a few weeks, based on the very occasional occurrence of leprosy among young infants. The maximum incubation period reported is as long as 30 years, or over, as observed among war veterans known to have been exposed for short periods in endemic areas but otherwise living in non-endemic areas. It is generally agreed that the average incubation period is between three and five years. Leprosy has affected humanity for over 4,000 years, and was recognized in the civilizations of ancient [13] China, Egypt, Israel, and India. In 1995, the World Health Organization (WHO) estimated that between 2 and 3 million [14] people were permanently disabled because of leprosy at that time. In the past 20 years, 15 million people worldwide [15] have been cured of leprosy. Although the forced quarantine or segregation of patients is unnecessary in places where adequate treatments are available, many leper colonies still remain around the world in countries such as India (where there are still more than 1,000 leper [15] [16] [17] [18] [19] colonies), China, Romania, Egypt, Nepal, Somalia, Liberia, Vietnam, and Japan. Leprosy was once believed to be highly contagious and was treated with mercury all of which applied to syphilis, which was first described in 1530. [20] It is possible that many early cases thought to be leprosy could have actually been syphilis. The age-old social stigma associated with the advanced form of leprosy lingers in many areas, and remains a major obstacle to self-reporting and early treatment. Effective treatment for leprosy appeared in the late 1930s with the introduction of dapsone and its derivatives. Leprosy bacilli resistant to dapsone soon evolved and, due to overuse of dapsone, became widespread. It was not until the introduction of multidrug therapy (MDT) in the early 1980s that the [22] disease could be diagnosed and treated successfully within the community. MDT for multibacillary leprosy consists of rifampicin, dapsone, and clofazimine taken over 12 months. Dosages adjusted [22] appropriately for children and adults are available in all primary health centres in the form of blister packages. Single dose MDT for single lesion leprosy consists of rifampicin,ofloxacin, and minocycline. The move toward single-dose treatment strategies has reduced the prevalence of disease in some regions, since prevalence is dependent on duration of treatment. World Leprosy Day was created to draw awareness to leprosy and its sufferers.
Contents
[hide]
[21] [12]

1 Classification 2 Signs and symptoms 3 Diagnosis 4 Cause

o o o

4.1 Mycobacterium leprae 4.2 Genetics 4.3 Risk factors

5 Pathophysiology 6 Prevention 7 Treatment

7.1 Historical treatments

7.1.1 Chaulmoogra oil

7.2 Modern drug treatment

8 Epidemiology

o o

8.1 Disease burden 8.2 Global situation

9 History

o o o o o o o o

9.1 Etymology 9.2 Ancient Rome 9.3 Iran 9.4 Middle Ages 9.5 India 9.6 China 9.7 Indonesia 9.8 Japan

10 Society and culture

o o

10.1 Stigma in India 10.2 Notable cases

11 See also 12 References 13 Further reading 14 External links

[edit]Classification There are several different approaches for classifying leprosy; however, parallels exist. The World Health Organization system distinguishes "paucibacillary" and "multibacillary" based upon the proliferation [23] of bacteria ("pauci-" refers to a low quantity.) The SHAY scale provides five gradations.
[24][25]

The ICD-10, though developed by the WHO, uses Ridley-Jopling and not the WHO system. It also adds an [26] indeterminate ("I") entry. In MeSH, three groupings are used. RidleyJopling ICD10 Immune target

WHO

MeSH

Description

Lepromintest

tuberculoid ("TT"), Paucibacillary borderline tuberculoid ("BT")

A30.1, Tuberculoid A30.2

It is characterized by one or more hypopigmented skin macules and anaesthetic patches, where skinsensations are lost because of damaged peripheral nerves that have been attacked by the human host's immune cells.

Positive

bacillus (Th1)

midborderline Multibacillary or borderline A30.3 Borderline ("BB")

Borderline leprosy is of intermediate severity and is the most common form. Skin lesions resemble tuberculoid leprosy but are more numerous and irregular; large patches may affect a whole limb, and peripheral nerve

involvement with weakness and loss of sensation is common. This type is unstable and may become more like lepromatous leprosy or may undergo a reversal reaction, becoming more like the tuberculoid form.

borderline lepromatous Multibacillary ("BL"), and lepromatous ("LL")

It is associated with symmetric skin lesions, nodules, plaques, thickened dermis, and frequent A30.4, involvement of the nasal mucosa Lepromatous A30.5 resulting in nasal congestion and epistaxis (nose bleeds), but, typically, detectable nerve damage is late.
[27]

Negative

plasmid inside [citation bacillus needed] (Th2)

There is a difference in immune response to the tuberculoid and lepromatous forms. Hansen's disease may also be divided into the following types: Early and indeterminate leprosy Tuberculoid leprosy Borderline tuberculoid leprosy Borderline leprosy Borderline lepromatous leprosy Lepromatous leprosy Histoid leprosy Diffuse leprosy of Lucio and Latap
[28]:344-346

This disease may also occur with only neural involvement, without skin lesions. known as Hansen's Disease. [edit]Signs

[13][29][30][31][32][33]

This disease is also

and symptoms
[3]

Skin lesions are the primary external sign. to the skin, nerves, limbs, and eyes. [edit]Diagnosis

Left untreated, leprosy can be progressive, causing permanent damage

Diagnosis in the U.S. is often delayed because healthcare providers are unaware of leprosy and its symptoms. Early [34] diagnosis and treatment prevents nerve involvement, the hallmark of leprosy, and the disability it causes. There are many kinds of leprosy but there are common symptoms, including: runny nose; dry scalp; eye problems; skin lesions; muscle weakness; reddish skin; smooth shiny diffuse thickening of facial skin, ear, and hand; loss of sensation in fingers and toes; thickening of peripheral nerves; and flat nose due to destruction of nasal cartilage. There is also phonation and resonation of sound during speech. Often there is atrophy of the testes and impotency. [edit]Cause [edit]Mycobacterium

leprae

Mycobacterium leprae, one of the causative agents of leprosy. As acid-fastbacteria, M. leprae appear red when aZiehl-Neelsen stain is used.

Main article: Mycobacterium leprae Mycobacterium leprae and Mycobacterium lepromatosis are the causative agents of leprosy. M. lepromatosis is a [2][3] relatively newly identified mycobacterium isolated from a fatal case of diffuse lepromatous leprosy in 2008. An intracellular, acid-fast bacterium, M. leprae is aerobic and rod-shaped, and is surrounded by the waxy cell [35] membrane coating characteristic ofMycobacterium species. Due to extensive loss of genes necessary for independent growth, M. leprae and M. lepromatosis are obligate pathogens, and unculturable in the laboratory, a factor that leads to difficulty in definitively identifying the organism [2][36] under a strict interpretation of Koch's postulates. The use of non-culture-based techniques such as molecular genetics has allowed for alternative establishment of causation. While the causative organisms have to date been impossible to culture in vitro, it has been possible to grow them in animals. Charles Shepard, chairman of the United States Leprosy Panel, successfully grew the organisms in the footpads of mice in 1960. This method was improved with the use of congenitally athymic mice (nude mice) in 1970 by Joseph Colson and Richard Hilson at St George's Hospital, London. A second animal model was developed by Eleanor Storrs at the Gulf South Research Institute. Dr Storrs had worked on the nine-banded armadillo for her PhD, because this animal had a lower body temperature than humans and might therefore be a suitable animal model. The work started in 1968 with material provided by Waldemar Kirchheimer at the United States Public Health Leprosarium in Carville, Louisiana. These experiments proved unsuccessful, but additional work in 1970 with material provided by Chapman Binford, medical director of the Leonard's Wood Memorial, was successful. The papers describing this model led to a dispute of priority. Further controversy was generated when it was discovered that wild armadillos in Louisiana were naturally infected with leprosy. Naturally occurring infection also has been reported in non-human primates including the African chimpanzee, sooty mangabey, and cynomolgus macaque. [edit]Genetics It is believed that around 95% of people are naturally immune. Recent research suggests that there is a defect in cell-mediated immunity that causes susceptibility to Hansen's disease. The region of DNA responsible for this variability is also involved in Parkinson disease, giving rise to current speculation that the two disorders may be linked [39] in some way at the biochemical level. Several genes have been associated with a susceptibility to leprosy:
[37][38]

Name

Locus

OMIM

Gene

LPRS1 10p13

609888

LPRS2 6q25

607572 PARK2, PACRG

LPRS3 4q32

246300 TLR2

LPRS4 6p21.3

610988 LTA

LPRS5 4p14

613223 TLR1

LPRS6 13q14.11 613407 [edit]Risk

factors

At highest risk are those living in endemic areas with poor conditions such as inadequate bedding, contaminated water, and insufficient diet, or other diseases that compromise immune function.

Professional studies show little evidence that HIV is an important factor in increasing the risk of leprosy [40][41] [42][43] infection, but the potential is under active review. [edit]Pathophysiology The mechanism of transmission of leprosy is prolonged close contact and transmission by nasal droplet. In addition to humans, leprosy has been observed in nine-banded armadillo, (which, it has recently been confirmed, are among [44] [45] the primary sources of new cases of leprosy in Americans ), and three species of primates. The bacterium can [46] also be grown in the laboratory by injection into the footpads of mice. There is evidence that not all people who are infected with M. leprae develop leprosy, and genetic factors have long been thought to play a role, due to the observation of clustering of leprosy around certain families, and the failure to understand why certain individuals [47] develop lepromatous leprosy while others develop other types of leprosy. It is estimated that due to genetic factors, [48] only 5% of the population is susceptible to leprosy. This is mostly because the body is naturally immune to the bacteria, and those persons that do become infected experience severe allergic reactions to the disease. However, the role of genetic factors is not entirely clear in determining this clinical expression. In addition, malnutrition and prolonged exposure to infected persons may play a role in development of the overt disease. The most widely held belief is that the disease is transmitted by contact between infected persons and healthy [49] persons. In general, closeness of contact is related to the dose of infection, which in turn is related to the occurrence of disease. Of the various situations that promote close contact, contact within the household is the only one that is easily identified, although the incidence among contacts and the relative risk for them appear to vary considerably in different studies. In incidence studies, infection rates for contacts of lepromatous leprosy have varied [50] from 6.2 per 1000 per year in Cebu, Philippines to 53 per 1000 per year in part of Western India to 55.8 per 1000 [51] per year in a part of Southern India. Two exit routes of M. leprae from the human body often described are the skin and the nasal mucosa, although their relative importance is not clear. Lepromatous cases show large numbers of organisms deep in the dermis, but [26] whether they reach the skin surface in sufficient numbers is doubtful. Although there are reports of acid-fast bacilli being found in the desquamatingepithelium (sloughing of superficial layer of skin) of the skin, Weddell et al. had reported in 1963 that they could not find any acid-fast bacilli in the epidermis, even after examining a very large [52] number of specimens from patients and contacts. In a recent study, Job et al. found fairly large numbers of M. leprae in the superficial keratin layer of the skin of lepromatous leprosy patients, suggesting that the organism could [53] exit along with the sebaceous secretions. The importance of the nasal mucosa was recognized as early as 1898 by Schffer, in particular that of the ulcerated [54] mucosa. The quantity of bacilli from nasal mucosal lesions in lepromatous leprosy was demonstrated by Shepard [55] as large, with counts ranging from 10,000 to 10,000,000. Pedley reported that the majority of lepromatous patients [56] showed leprosy bacilli in their nasal secretions as collected through blowing the nose. Davey and Rees indicated [57] that nasal secretions from lepromatous patients could yield as much as 10 million viable organisms per day. The entry route of M. leprae into the human body is also not definitively known: The skin and the upper respiratory tract are most likely. While older research dealt with the skin route, recent research has increasingly favored the respiratory route. Rees and McDougall succeeded in the experimental transmission of leprosy through aerosols [58] containing M. leprae in immune-suppressed mice, suggesting a similar possibility in humans. Successful results have also been reported on experiments with nude mice when M. leprae were introduced into the nasal cavity by [59] topical application. In summary, entry through the respiratory route appears the most probable route, although other routes, particularly broken skin, cannot be ruled out. The CDC notes the following assertion about the transmission of the disease: "Although the mode of transmission of Hansen's disease remains uncertain, most [60] investigators think that M. leprae is usually spread from person to person in respiratory droplets." In leprosy, both the reference points for measuring the incubation period and the times of infection and onset of disease are difficult to define, the former because of the lack of adequate immunological tools and the latter because of the disease's slow onset. Even so, several investigators have attempted to measure the incubation period for leprosy. The minimum incubation period reported is as short as a few weeks and this is based on the very occasional [61] occurrence of leprosy among young infants. The maximum incubation period reported is as long as 30 years, or over, as observed among war veterans known to have been exposed for short periods in endemic areas but otherwise living in non-endemic areas. It is generally agreed that the average incubation period is between three and five years. [edit]Prevention In a recent trial, a single dose of rifampicin reduced the rate at which contacts acquired leprosy in the two years after [62] contact by 57%; 265 treatments with rifampicin prevented one case of leprosy in this period. A non-randomized [63] study found that rifampicin reduced the number of new cases of leprosy by 75% after three years.
[13]

BCG offers a variable amount of protection against leprosy as well as against tuberculosis.

[64][65]

Efforts to overcome persistent obstacles to the elimination of the disease include improving detection, educating patients and the population about its cause, and fighting social taboos about a disease that has caused its patients throughout history to be considered "unclean" or "cursed by God" as outcasts. Leprosy is not a hereditary disease. Where taboos are strong, patients may be forced to hide their condition (and avoid seeking treatment) to avoid discrimination. The lack of awareness about Hansen's disease can lead people to believe (falsely) that the disease is highly contagious and incurable. The ALERT hospital and research facility in Ethiopia provides training to medical personnel from around the world in the treatment of leprosy, as well as treating many local patients. Surgical techniques, such as for the restoration of control of movement of thumbs, have been developed. [edit]Treatment In 1988, Jacinto Convit was nominated for the Nobel Prize in Medicine, for developing a vaccine to fight leprosy, by combining a tuberculosis (TB) vaccines with Mycobacterium Leprae.

MDT anti-leprosy drugs: standard regimens

Enough synthetic pharmaceuticals that are effective against leprosy have by now been identified, and support a flexible choice of treatments. The WHO Study Group's report on the Chemotherapy of Leprosy in 1993 recommended [66] two types of standard MDT regimen be adopted. The first was a 24-month treatment for multibacillary (MB or lepromatous) cases using rifampicin, clofazimine, and dapsone. The second was a six-month treatment for paucibacillary (PB or tuberculoid) cases, using rifampicin and dapsone. At the First International Conference on the Elimination of Leprosy as a Public Health Problem, held in Hanoi the next year, the global strategy was endorsed and funds provided to WHO for the procurement and supply of MDT to all endemic countries. Between 1995 and 1999, WHO, with the aid of the Nippon Foundation (Chairman Yhei Sasakawa, World Health Organization Goodwill Ambassador for Leprosy Elimination), supplied all endemic countries with free MDT in blister packs, channelled through Ministries of Health. This free provision was extended in 2000 and again in 2005 with donations by the MDT manufacturer Novartis through WHO. In the latest agreement signed between the company and WHO in October 2010, the provision of free MDT by WHO to all endemic countries will now run until at least the end of 2015. At the national level, non-government organizations (NGOs) affiliated to the national programme will continue to be provided with an appropriate free supply of this WHO supplied MDT by the government. MDT remains highly effective, and patients are no longer infectious after the first monthly dose. It is safe and easy [13] to use under field conditions due to its presentation in calendar blister packs. Relapse rates remain low, and there [13] [67] is no known resistance to the combined drugs. The Seventh WHO Expert Committee on Leprosy, reporting in 1997, concluded that the MB duration of treatment then standing at 24 months could safely be shortened to 12 months "without significantly compromising its efficacy."
[13]

Schistosomiasis (also known as bilharzia, bilharziosis or snail fever) is a parasitic disease caused by several species of trematodes(platyhelminth infection, or "flukes"), a parasitic worm of the genus Schistosoma. Snails serve as the intermediary agent between mammalian hosts. Individuals within developing countries who cannot afford proper water [1] and sanitation facilities are often exposed to contaminated water containing the infected snails. Although it has a low mortality rate, schistosomiasis often is a chronic illness that can damage internal organs and, in children, impair growth andcognitive development. The urinary form of schistosomiasis is associated with increased risks for bladder cancer in adults. Schistosomiasis is the second most socioeconomically devastating parasitic disease [2] after malaria. This disease is most commonly found in Asia, Africa, and South America, especially in areas where the water contains numerous freshwater snails, which may carry the parasite. The disease affects many people in developing countries, particularly children who may acquire the disease by swimming [2] or playing in infected water. When children come into contact with a contaminated water source, the parasitic larvae easily enter through their skin and further mature within organ tissues. As of 2009, 74 developing [1] countries statistically identified epidemics of Schistosomiasis within their respective populations.
Contents
[hide]

1 Classification 2 Signs and symptoms 3 Pathophysiology

3.1 Life cycle

4 Diagnosis

3.1.1 Snails 3.1.2 Humans

5 Prevention

5.1 Eliminating or avoiding the snails

6 Treatment 7 Epidemiology 8 History 9 Society and culture

9.1 Egypt treatment campaign and Hepatitis C

10 See also 11 References 12 Further reading 13 External links

[edit]Classification Species of Schistosoma that can infect humans: Schistosoma mansoni (ICD-10 B65.1) and Schistosoma intercalatum (B65.8) cause intestinal schistosomiasis Schistosoma haematobium (B65.0) causes urinary schistosomiasis Schistosoma japonicum (B65.2) and Schistosoma mekongi (B65.8) cause Asian intestinal schistosomiasis

Avian schistosomiasis species cause swimmer's itch and clam digger itch Species of Schistosoma that can infect other animals: S. bovis normally infects cattle, sheep and goats in Africa, parts of Southern Europe and the Middle East S. mattheei normally infects cattle, sheep and goats in Central and Southern Africa S. margrebowiei normally infects antelope, buffalo and waterbuck in Southern and Central Africa S. curassoni normally infects domestic ruminants in West Africa S. rodhaini normally infects rodents and carnivores in parts of Central Africa

[edit]Signs

and symptoms

Above all, schistosomiasis is a chronic disease. Many infections are subclinically symptomatic, with mild anemia and malnutrition being common in endemic areas. Acute schistosomiasis (Katayama's fever) may occur weeks after the initial infection, especially by S. mansoni and S. japonicum. Manifestations include: Abdominal pain Cough Diarrhea Eosinophilia extremely high eosinophil granulocyte (white blood cell) count. Fever Fatigue Hepatosplenomegaly the enlargement of both the liver and the spleen. Hepatic schistosomiasis is the second most [3] common cause of esophageal varices worldwide. Genital sores lesions that increase vulnerability to HIV infection. Lesions caused by schistosomiasis may continue to be a problem after control of the schistosomiasis infection itself. Early treatment, especially of children, which is [4][5] relatively inexpensive, prevents formation of the sores. Skin symptoms: At the start of infection, mild itching and a papular dermatitis of the feet and other parts after [6]:432 swimming in polluted streams containing cercariae.

Occasionally central nervous system lesions occur: cerebral granulomatous disease may be caused by ectopic S. japonicum eggs in the brain, and granulomatous lesions around ectopic eggs in the spinal cord from S. mansoni and S. haematobium infections may result in a transverse myelitis with flaccid paraplegia.

Calcification of the bladder wall on a plain x-ray image of the pelvis, in a sub-Saharan man of 44 years old. This is due to urinary schistosomiasis.

Continuing infection may cause granulomatous reactions and fibrosis in the affected organs, which may result in manifestations that include: Colonic polyposis with bloody diarrhea (Schistosoma mansoni mostly); Portal hypertension with hematemesis and splenomegaly (S. mansoni, S. japonicum); Cystitis and ureteritis (S. haematobium) with hematuria, which can progress to bladder cancer; Pulmonary hypertension (S. mansoni, S. japonicum, more rarely S. haematobium); Glomerulonephritis; and central nervous system lesions.

Bladder cancer diagnosis and mortality are generally elevated in affected areas. [edit]Pathophysiology [edit]Life

cycle

Schistosoma life cycle. Source: CDC

Schistosomes have a typical trematode vertebrate-invertebrate lifecycle, with humans being the definitive host. [edit]Snails The life cycles of all five human schistosomes are broadly similar: parasite eggs are released into the environment from infected individuals, hatching on contact with fresh water to release the free-swimming miracidium. Miracidia infect freshwater snails by penetrating the snail's foot. After infection, close to the site of penetration, the miracidium transforms into a primary (mother) sporocyst. Germ cells within the primary sporocyst will then begin dividing to produce secondary (daughter) sporocysts, which migrate to the snail's hepatopancreas. Once at the hepatopancreas, germ cells within the secondary sporocyst begin to divide again, this time producing thousands of new parasites, known as cercariae, which are the larvae capable of infecting mammals. Cercariae emerge daily from the snail host in a circadian rhythm, dependent on ambient temperature and light. Young cercariae are highly mobile, alternating between vigorous upward movement and sinking to maintain their position in the water. Cercarial activity is particularly stimulated by water turbulence, by shadows and by chemicals found on human skin. [edit]Humans Penetration of the human skin occurs after the cercaria have attached to and explored the skin. The parasite secretes enzymes that break down the skin's protein to enable penetration of the cercarial head through the skin. As the cercaria penetrates the skin it transforms into a migrating schistosomulum stage.

Photomicrography of bladder inS. hematobium infection, showing clusters of the parasite eggs with intense eosinophilia, Source: CDC

The newly transformed schistosomulum may remain in the skin for two days before locating a post-capillary venule; from here the schistosomulum travels to the lungs where it undergoes further developmental changes necessary for subsequent migration to the liver. Eight to ten days after penetration of the skin, the parasite migrates to the liver sinusoids. S. japonicum migrates more quickly than S. mansoni, and usually reaches the liver within eight days of penetration. Juvenile S. mansoni and S. japonicum worms develop an oral sucker after arriving at the liver, and it is during this period that the parasite begins to feed on red blood cells. The nearly-mature worms pair, with the longer female worm residing in the gynaecophoric channel of the shorter male. Adult worms are about 10 mm long. Worm pairs of S. mansoni and S. japonicum relocate to the mesenteric or rectal veins.S. haematobium schistosomula ultimately migrate from the liver to the perivesical venous plexus of the bladder, ureters, and kidneys through the hemorrhoidal plexus. Parasites reach maturity in six to eight weeks, at which time they begin to produce eggs. Adult S. mansoni pairs residing in the mesenteric vessels may produce up to 300 eggs per day during their reproductive lives. S. japonicum may produce up to 3,000 eggs per day. Many of the eggs pass through the walls of the blood vessels, and through the intestinal wall, to be passed out of the body in feces. S. haematobium eggs pass through the ureteral or bladder wall and into the urine. Only mature eggs are capable of crossing into the digestive tract, possibly through the release of proteolyticenzymes, but also as a function of host immune response, which fosters local tissue ulceration. Up to half the eggs released by the worm pairs become trapped in the mesenteric veins, or will be washed back into the liver, where they will become lodged. Worm pairs can live in the body for an average of four and a half years, but may persist up to twenty years. Trapped eggs mature normally, secreting antigens that elicit a vigorous immune response. The eggs themselves do not damage the body. Rather it is the cellular infiltration resultant from the immune response that causes the pathology classically associated with schistosomiasis. [edit]Diagnosis

High powered detailed micrograph ofSchistosoma parasite eggs in human bladder tissue.

S. japonicum eggs in hepatic portal tract.

Microscopic identification of eggs in stool or urine is the most practical method for diagnosis. The stool exam is the more common of the two. For the measurement of eggs in the feces of presenting patients the scientific unit used is eggs per gram (epg). Stool examination should be performed when infection with S. mansoni or S. japonicum is suspected, and urine examination should be performed if S. haematobium is suspected. Eggs can be present in the stool in infections with all Schistosoma species. The examination can be performed on a simple smear (1 to 2 mg of fecal material). Since eggs may be passed intermittently or in small amounts, their detection will be enhanced by repeated examinations and/or concentration procedures (such as the formalin-ethyl acetate technique). In addition, for field surveys and investigational purposes, the egg output can be quantified by using the KatoKatz technique (20 to 50 mg of fecal material) or the Ritchie technique. Eggs can be found in the urine in infections with S. japonicum and with S. intercalatum (recommended time for collection: between noon and 3 p.m.) Detection will be enhanced by centrifugation and examination of the sediment. Quantification is possible by using filtration through a nucleoporemembrane of a standard volume of urine followed by egg counts on the membrane. Investigation of S. haematobium should also include a pelvic x-ray as bladder wall calcificaition is highly characteristic of chronic infection. Recently a field evaluation of a novel handheld microscope was undertaken in Uganda for the diagnosis of intestinal schistosomiasis by a team led by Dr. Russell Stothard from the Natural History Museum of London, working with the [7] Schistosomiasis Control Initiative, London. Tissue biopsy (rectal biopsy for all species and biopsy of the bladder for S. haematobium) may demonstrate eggs when stool or urine examinations are negative. The eggs of S. haematobium are ellipsoidal with a terminal spine, S. mansoni eggs are also ellipsoidal but with a lateral spine, S. japonicum eggs are spheroidal with a small knob. Antibody detection can be useful in both clinical management and for epidemiologic surveys. [edit]Prevention [edit]Eliminating

or avoiding the snails

Prevention is best accomplished by eliminating the water-dwelling snails that are the natural reservoir of the disease. Acrolein, copper sulfate, and niclosamide can be used for this purpose. Recent studies have suggested that snail populations can be controlled by the introduction of, or augmentation of existing, crayfish populations; as with all ecological interventions, however, this technique must be approached with caution. In 1989, Aklilu Lemma and Legesse Wolde-Yohannes received the Right Livelihood Award for their research on the sarcoca plant, as a preventative measure for the disease by controlling the snail. Concurrently, Dr. Chidzere of

Zimbabwe researched the similar gopo berry during the 1980s and found that it could be used in the control of infected freshwater snails. In 1989 he drew attention to his concerns that big chemical companies denigrated the gopo berry [8] alternative for snail control. Gopo berries from hotter Ethiopia climates reputedly yield the best results. Later studies [9][10] were conducted between 1993 and 1995 by the Danish Research Network for international health. For many years from the 1950s onwards, civil engineers built vast dam and irrigation schemes, oblivious to the fact that they would cause a massive rise in water-borne infections from schistosomiasis. The detailed specifications laid out in various UN documents since the 1950s could have minimized this problem. Irrigation schemes can be designed to make it hard for [11] the snails to colonize the water, and to reduce the contact with the local population. This has been cited as a classic case of the relevance paradox because guidelines on how to design these schemes to [12] minimise the spread of the disease had been published years before, but the designers were unaware of them. [edit]Treatment Main article: Schistosomicide Schistosomiasis is readily treated using a single oral dose of the drug praziquantel annually. As with other major parasitic diseases, there is ongoing and extensive research into developing aschistosomiasis vaccine that will prevent the parasite from completing its life cycle in humans. In 2009, Eurogentec Biologics developed a vaccine against bilharziosis [14][15][16] in partnership with INSERMand researchers from the Pasteur Institute. The World Health Organization has developed guidelines for community treatment of schistosomiasis based on the [13] impact the disease has on children in endemic villages: When a village reports more than 50 percent of children have blood in their urine, everyone in the village receives [13] treatment. When 20 to 50 percent of children have bloody urine, only school-age children are treated.
[13] [13] [13]

When less than 20 percent of children have symptoms, mass treatment is not implemented.

The Bill & Melinda Gates Foundation has recently funded an operational research program---the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) to answer strategic questions about how to move forward with schistosomiasis control and elimination. The focus of SCORE is on development of tools and evaluation of strategies for use in mass drug administration campaigns. Antimony has been used in the past to treat the disease. In low doses, this toxic metalloid bonds to sulfur atoms in enzymes used by the parasite and kills it without harming the host. This treatment is not referred to in present-day peerreview scholarship; praziquantel is universally used. Outside of the U.S., there is a drug available exclusively for treating Schistosoma mansoni(oxamniquine) and one exclusively for treating S.hematobium (metrifonate). While metrifonate has been discontinued for use by the British National Health Service, a Cochrane review found it equally [17] effective in treating urinary schistosomiasis as the leading drug, praziquantel. Mirazid, an Egyptian drug made from myrrh, was under investigation for oral treatment of the disease up until [18] 2005. The efficacy of praziquantel was proven to be about 8 times than that of Mirazid and therefore Mirazid was not [19] recommended as a suitable agent to control schistosomiasis.

Filariasis (philariasis) is a parasitic disease (usually an infectious tropical disease) that is caused by thread[1] [2] like nematodes (roundworms) belonging to the superfamily Filarioidea, also known as "filariae". These are transmitted from host to host by blood-feeding arthropods, mainly black flies andmosquitoes. Eight known filarial nematodes use humans as their definitive hosts. These are divided into three groups according to the niche within the body they occupy: 'lymphatic filariasis', 'subcutaneous filariasis', and 'serous cavity filariasis'. Lymphatic filariasis is caused by the worms Wuchereria bancrofti, Brugia malayi, and Brugia timori. These worms occupy the lymphatic system, including the lymph nodes, and in chronic cases these worms lead to the disease elephantiasis. Subcutaneous filariasis is caused by Loa loa (the eye worm), Mansonella streptocerca, and Onchocerca volvulus. These worms occupy the subcutaneous layer of the skin, in the fat layer. L. loa causes Loa loa filariasis while O. volvulus causes river blindness. Serous cavity filariasis is caused by the worms Mansonella perstans and Mansonella ozzardi, which occupy the serous cavity of theabdomen.

The adult worms, which usually stay in one tissue, release early larvae forms known as microfilariae into the host's bloodstream. These circulating microfilariae can be taken up with a blood meal by the arthropod vector; in the vector they develop into infective larvae that can be transmitted to a new host. Individuals infected by filarial worms may be described as either "microfilaraemic" or "amicrofilaraemic", depending on whether or not microfilaria can be found in their peripheral blood. Filariasis is diagnosed in microfilaraemic cases primarily through direct observation of microfilaria in the peripheral blood. Occult filariasis is diagnosed in amicrofilaraemic cases based on clinical observations and, in some cases, by finding a circulating antigen in the blood.
Contents
[hide]

1 Signs and symptoms 2 Diagnosis

2.1 Concentration methods

3 Worm lifecycle 4 Prevention 5 Treatment 6 Epidemiology 7 History 8 In other animals

o o o

8.1 In cattle 8.2 In horses 8.3 In dogs

9 See also 10 References 11 Further reading 12 External links

[edit]Signs

and symptoms

The most spectacular symptom of lymphatic filariasis is elephantiasisedema with thickening of the skin and underlying [3] tissueswhich was the first disease discovered to be transmitted by mosquito bites. Elephantiasis results when the parasites lodge in the lymphatic system. Elephantiasis affects mainly the lower extremities, while the ears, mucous membranes, and amputation stumps are affected less frequently. However, different species of filarial worms tend to affect different parts of the body: Wuchereria [3] bancrofti can affect the legs, arms, vulva, breasts, and scrotum (causing hydrocele formation), while Brugia timori rarely [citation needed] affects the genitals. Interestingly, those who develop the chronic stages of elephantiasis are usually [citation amicrofilaraemic, and often have adverse immunological reactions to the microfilaria, as well as the adult worms.
needed]

The subcutaneous worms present with skin rashes, urticarial papules, and arthritis, as well as hyper- and hypopigmentation macules. Onchocerca volvulus manifests itself in the eyes, causing "river blindness" (onchocerciasis), [citation needed] one of the leading causes of blindness in the world. Serous cavity filariasis presents with symptoms similar to subcutaneous filariasis, in addition to abdominal pain, because these worms are also deep tissue dwellers. [edit]Diagnosis Filariasis is usually diagnosed by identifying microfilariae on Giemsa stained, thin and thick blood film smears, using the "gold standard" known as the finger prick test. The finger prick test draws blood from the capillaries of the finger tip; larger veins can be used for blood extraction, but strict windows of the time of day must be observed. Blood must be drawn at appropriate times, which reflect the feeding activities of the vector insects. Examples are W. bancrofti, whose vector is a mosquito; night time is the preferred time for blood collection. Loa loa's vector is the deer fly; daytime collection is preferred. This method of diagnosis is only relevant to microfilariae that use the blood as transport from the lungs to the skin. Some filarial worms, such as M. streptocercaand O. volvulus, produce microfilarae that do not use the blood; they reside in the skin only. For these worms, diagnosis relies upon skin snips, and can be carried out at any time. [edit]Concentration

methods

This section needs additionalcitations for verification. (May

2010)

Various concentration methods are applied: membrane filter, Knott's concentration method, and sedimentation technique. Polymerase chain reaction (PCR) and antigenic assays, which detect circulating filarial antigens, are also available for making the diagnosis. The latter are particularly useful in amicrofilaraemic cases. Spot tests for antigen [1] are far more sensitive, and allow the test to be done any time, rather in the late hours. Lymph node aspirate and chylus fluid may also yield microfilariae. Medical imaging, such as CT or MRI, may reveal "filarial dance sign" in chylus fluid; X-ray tests can show calcified adult worms in lymphatics. The DEC provocation test is performed to obtain satisfying number of parasite in day-time samples. Xenodiagnosis is now obsolete, and eosinophilia is a nonspecific primary sign. [edit]Worm

lifecycle

Human filarial nematode worms have complicated life cycles, which primarily consists of five stages. After the male and female worms mate, the female gives birth to live microfilariae by the thousands. The microfilariae are taken up by the vector insect (intermediate host) during a blood meal. In the intermediate host, the microfilariae molt and develop into third-stage (infective) larvae. Upon taking another blood meal, the vector insect injects the infectious larvae into the dermis layer of the skin. After about one year, the larvae molt through two more stages, maturing into the adult worms. [edit]Prevention In 1993, the International Task Force for Disease Eradication declared lymphatic filariaisis to be one of six [4] potentially eradicable diseases. Studies have demonstrated transmission of the infection can be broken when a single [5] dose of combined oral medicines is consistently maintained annually for approximately seven years. With consistent treatment, and since the disease needs a human host, the reduction of microfilariae means the disease will not be [5] transmitted, the adult worms will die out, and the cycle will be broken. The strategy for eliminating transmission of lymphatic filariasis is mass distribution of medicines that kill the microfilariae [5] and stop transmission of the parasite by mosquitoes in endemic communities. In sub-Saharan Africa, albendazole (donated by GlaxoSmithKline) is being used with ivermectin (donated by Merck & Co.) to treat the [4] disease, whereas elsewhere in the world albendazole is used with diethylcarbamazine. Using a combination of [5] treatments better reduces the number of microfilariae in blood. Avoiding mosquito bites, such as by using insecticide[5][6] treated mosquito bed nets, also reduces the transmission of lymphatic filariasis. The efforts of the Global Programme to Eliminate LF are estimated to have prevented 6.6 million new filariasis cases from developing in children between 2000 and 2007, and to have stopped the progression of the disease in another 9.5 [7] million people who had already contracted it. Dr. Mwele Malecela, who chairs the programme, said: "We are on track to [8] accomplish our goal of elimination by 2020." In 2010, the WHO published a detailed progress report on the elimination campaign in which they assert that of the 81 countries with endemic LF, 53 have implemented mass drug administration, [9] and 37 have completed five or more rounds in some areas, though urban areas remain problematic. [edit]Treatment

The recommended treatment for patients outside the United States is albendazole (a broad spectrum anthelmintic) [4][10] [4] combined with ivermectin. A combination of diethylcarbamazine (DEC) and albendazole is also effective. All of these treatments are microfilaricides; they have no effect on the adult worms. In 2003, the common antibiotic doxycycline was suggested for treating elephantiasis. Filarial parasites have symbiotic bacteria in the genus Wolbachia, which live inside the worm and which seem to play a major role in both its reproduction and the development of the disease. Clinical trials in June 2005 by the Liverpool School of Tropical Medicine reported an [12][13] eight-week course almost completely eliminated microfilaraemia.
[11]

Malaria is a mosquito-borne infectious disease of humans and other animals caused by protists (a type of microorganism) of the genus Plasmodium. The protists first infect the liver, then act as parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases progressing to coma or death. The disease is widespread in tropical and subtropical regions in a broad band around the equator, including much of Sub-Saharan Africa, Asia, and the Americas. Five species of Plasmodium can infect and be transmitted by humans. The vast majority of deaths are caused by P. falciparum while P. vivax,P. ovale, and P. malariae cause a generally milder form of malaria that is rarely fatal. The zoonotic species P. knowlesi, prevalent in Southeast Asia, causes malaria in macaques but can also cause severe infections in humans. Malaria is prevalent in tropical regions because the significant amounts of rainfall, consistently high temperatures and high humidity, along with stagnant waters in which mosquito larvae readily mature, provide them with the environment they need for continuous breeding. Disease transmission can be reduced by preventing mosquito bites by distribution of mosquito nets and insect repellents, or with mosquito-control measures such as spraying insecticides and draining standing water. The World Health Organization has estimated that in 2010, there were 216 million documented cases of malaria. Around [1] 655,000 people died from the disease, many of whom were children under the age of five. The actual number of deaths may be significantly higher, as precise statistics are unavailable in many rural areas, and many cases are undocumented. Malaria is commonly associated with poverty and is also a major hindrance toeconomic development. Despite a clear need, no vaccine offering a high level of protection currently exists. Efforts to develop one are ongoing. Several medications are available to prevent malaria in travelers to malaria-endemic countries (prophylaxis). A variety of antimalarial medications are available. Severe malaria is treated with intravenous or intramuscular quinine or, since the mid-2000s, the artemisinin derivative artesunate, which is superior to quinine in both children and adults and is given in combination with a second anti-malarial such as mefloquine. Resistance has developed to several antimalarial drugs, most notably chloroquine and artemisinin.
Contents
[hide]

1 Signs and symptoms

1.1 Complications

2 Cause

o o

2.1 Life cycle 2.2 Recurrent malaria

3 Pathogenesis

o o

3.1 Genetic resistance 3.2 Malarial hepatopathy

4 Diagnosis

4.1 Classification

5 Prevention

5.1 Vector control

o o

5.1.1 Indoor residual spraying 5.1.2 Mosquito nets

5.2 Other methods 5.3 Medications

6 Treatment

o o

6.1 Uncomplicated malaria 6.2 Severe malaria

7 Prognosis 8 Epidemiology 9 History 10 Society and culture

o o o o

10.1 Economic impact 10.2 Counterfeit and substandard drugs 10.3 War 10.4 Eradication efforts

11 Research

11.1 Immunization

12 In other animals 13 See also 14 References 15 Further reading 16 External links

[edit]Signs

and symptoms

Main symptoms of malaria.[2]

The typical fever patterns of the different types of malaria

The signs and symptoms of malaria typically begin 825 days following infection. However, symptoms may occur later in [4] those who have taken antimalarial medications as prevention. The presentation may include fever, shivering, arthralgia (joint pain), vomiting,hemolytic anemia, jaundice, hemoglobinuria, retinal [5] damage, and convulsions. Approximately 30% of people however will no longer have a fever upon presenting to a health [4] care facility. The classic symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting about two hours or more, occurring every two days in P. vivax and P. ovale infections, and every three days for P. malariae. P. falciparum infection can cause recurrent fever every 3648 hours or a less pronounced and almost

[3]

continuous fever. For reasons that are poorly understood, but that may be related to high intracranial pressure, children [7] with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. Cerebral malaria (encephalopathy specifically related to P. falciparum infection) is associated with retinal whitening, which may be a useful [8] clinical sign in distinguishing malaria from other causes of fever. Severe malaria is usually caused by P. falciparum, and typically arises 614 days after infection. Non-falciparum species [4] have however been found to be the cause of ~14% of cases of severe malaria in some groups. Consequences of severe malaria include coma and death if untreatedyoung children and pregnant women are especially vulnerable. Splenomegaly (enlarged spleen), severe headache, cerebral ischemia, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur. Renal failure is a feature of blackwater fever, where [9] hemoglobin from lysed red blood cells leaks into the urine. [edit]Complications There are a number of serious complications of malaria. Among these is the development of respiratory distress which [10] occurs in up to 25% of adults and 40% of children with falciparum malaria. The causes of this problem are diverse and include respiratory compensation of metabolic acidosis, noncardiogenic pulmonary oedema, concomitant pneumonia and severe anaemia. Acute respiratory distress syndrome (ARDS) may develop in 525% in adults and up to 29% of pregnant women but is rare in young children. [edit]Cause
[9]

[6]

A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-colour electron micrograph.

Malaria parasites are from the genus Plasmodium (phylum Apicomplexa). In humans, malaria is caused [11][12] by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. Among those infected,P. falciparum is the most [4] common species identified (~75%) followed by P. vivax (~20%). P. falciparum accounts for the majority of [13] [14] deaths. P. vivax proportionally is more common outside of Africa. There have been documented human infections with several species of Plasmodium fromhigher apes; however, with the exception of P. knowlesia zoonotic species that [12] [15] causes malaria inmacaques these are mostly of limited public health importance. [edit]Life

cycle

The definitive hosts for malaria parasites are female mosquitoes of the Anopheles genus, which act as transmission vectors to humans and other vertebrates, the secondary hosts. Young mosquitoes first ingest the malaria parasite by feeding on an infected vertebrate carrier and the infectedAnopheles mosquitoes eventually carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected vertebrate. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or [16] female gametes and then fuse in the mosquito's gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a [16] subsequent blood meal. This type of transmission is occasionally referred to as anterior station transfer. Only female mosquitoes feed on blood; male mosquitoes feed on plant nectar, and thus do not transmit the disease. The females of the Anophelesgenus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and [17] will continue throughout the night until taking a meal. Malaria parasites can also be transmitted by blood transfusions, [18] although this is rare. [edit]Recurrent

malaria

Malaria recurs after treatment for three reasons. Recrudescence occurs when parasites are not cleared by treatment, whereas reinfection indicates complete clearance with new infection established from a separate infective mosquito bite; both can occur with any malaria parasite species. Relapse is specific to P. vivax and P. ovale and involves re-emergence [4] of blood-stage parasites from latent parasites (hypnozoites) in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, [9] be deceptive. The longest incubation period reported for a P. vivax infection is 30 years. Approximately one in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites, with relapses beginning the year after [19] the mosquito bite. [edit]Pathogenesis Further information: Plasmodium falciparum biology

The life cycle of malaria parasites: A mosquito causes infection by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells, where they multiply into merozoites, rupture the liver cells, and return to the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts that in turn produce further merozoites. Sexual forms are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.

Malaria infection develops via two phases: one that involves the liver or hepatic system (exoerythrocytic), and one which involves red blood cells, or erythrocytes (erythrocytic). When an infected mosquito pierces a person's skin to take a blood meal, sporozoites in the mosquito's saliva enter the bloodstream and migrate to the liver where they infect hepatocytes, [20] multiplying asexually and asymptomatically for a period of 830 days. After a potential dormant period in the liver, these organisms differentiate to yield thousands of merozoites, which, following rupture of their host cells, escape into the blood and infect red blood cells to begin the erythrocytic stage of the [20] life cycle. The parasite escapes from the liver undetected by wrapping itself in thecell membrane of the infected host [21] liver cell. Within the red blood cells, the parasites multiply further, again asexually, periodically breaking out of their hosts to invade fresh red blood cells. Several such amplification cycles occur. Thus, classical descriptions of waves of fever arise from [20] simultaneous waves of merozoites escaping and infecting red blood cells. Some P. vivax sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (612 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long [22] incubation and late relapses in P. vivax infections, although their existence in P. ovale is uncertain. The parasite is relatively protected from attack by the body's immune system because for most of its human life cycle it resides within the liver and blood cells and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the P. falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thereby [23] sequestering the parasite from passage through the general circulation and the spleen. The blockage of the microvasculature causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red [24] blood cells can breach the bloodbrain barrier possibly leading to coma.

Micrograph of a placenta from a stillbirthdue to maternal malaria. H&E stain. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites

Although the red blood cell surface adhesive proteins (called PfEMP1, for P. falciparum erythrocyte membrane protein 1) are exposed to the immune system, they do not serve as good immune targets, because of their extreme diversity; there are at least 60 variations of the protein within a single parasite and even more variants within whole parasite [23] populations. The parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step [25] ahead of the pursuing immune system. Some merozoites turn into male and female gametocytes. If a mosquito pierces the skin of an infected person, it potentially picks up gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes, and malaria in pregnant women is an important cause [26] of stillbirths, infant mortality and low birth weight, particularly in P. falciparum infection, but also in other species [27] infection, such asP. vivax. [edit]Genetic

resistance

Main article: Genetic resistance to malaria Due to the high levels of mortality and morbidity caused by malariaespecially the P. falciparum speciesit is thought to have placed the greatestselective pressure on the human genome in recent history. Several diseases may provide some resistance to it including sickle cell disease,thalassaemias, glucose-6-phosphate dehydrogenase deficiency as well as the [28][29] presence of Duffy antigens on the subject's red blood cells. The impact of sickle cell anemia on malaria immunity is of particular interest. Sickle cell anemia causes a defect to the hemoglobin molecule in the blood. Instead of retaining the biconcave shape of a normal red blood cell, the modified hemoglobin S molecule causes the cell to sickle or distort into a curved shape. Due to the sickle shape, the molecule is not as effective in taking or releasing oxygen, and therefore malaria parasites cannot complete their life cycle in the cell. Individuals who are homozygous for sickle cell anemia seldom survive this defect, while those who are heterozygous experience immunity to the disease. Although the potential risk of death for those with the homozygous condition seems to be unfavorable to population survival, the trait is preserved because of the benefits provided by the heterozygous [30] form. [edit]Malarial

hepatopathy

Hepatic dysfunction as a result of malaria is rare and is usually a result of a coexisting liver condition such as viral [31] hepatitis and chronic liver disease. Hepatitis, which is characterized by inflammation of the liver, is not actually present in what is called malarial hepatitis; the term as used here invokes the reduced liver function associated with severe [31] malaria. While traditionally considered a rare occurrence, malarial hepatopathy has seen an increase in malaria [31] endemic areas, particularly in Southeast Asia and India. Liver compromise in people with malaria correlates with a [31] greater likelihood of complications and death. [edit]Diagnosis Main article: Diagnosis of malaria Malaria is typically diagnosed by the microscopic examination of blood using blood films or using antigen-based rapid [32][33] diagnostic tests. Rapid diagnostic tests that detect P. vivax are not as effective as those [34] [4] targeting P. falciparum. They also are unable to tell how many parasites are present. Areas that cannot afford laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for [35] malaria. Polymerase chain reaction based tests have been developed, though these are not widely implemented in [4] malaria-endemic regions as of 2012, due to their complexity. [edit]Classification

Malaria is divided into severe and uncomplicated by the World Health Organization (WHO). [36] when any of the following criteria are present, otherwise it is considered uncomplicated. Decreased consciousness Significant weakness such that the person is unable to walk Inability to feed Two or more convulsions Low blood pressure (less than 70 mmHg in adults or 50 mmHg in children) Breathing problems Circulatory shock Kidney failure or hemoglobin in the urine Bleeding problems, or hemoglobin less than 5 g/dl Pulmonary edema Low blood glucose (less than 2.2 mmol/l / 40 mg/dl) Acidosis or lactate levels of greater than 5 mmol/l A parasite level in the blood of greater than 2%

[4]

Severe malaria is diagnosed

[edit]Prevention

Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria, and mosquito control is an effective way of reducing the incidence of malaria.

Methods used to prevent malaria include medications, mosquito eradication and the prevention of bites. The presence of malaria in an area requires a combination of high human population density, high mosquito population density and high rates of transmission from humans to mosquitoes and from mosquitoes to humans. If any of these is lowered sufficiently, the parasite will eventually disappear from that area, as happened in North America, Europe and much of the Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a [37] combination that favours the parasite's reproduction. Many countries are seeing an increasing number of imported [38] malaria cases owing to extensive travel and migration. Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costsrequired are out of reach of many of the world's poorest people. There is a wide disparity in the costs of control (i.e. maintenance of low endemicity) and elimination programs between countries. For example, in Chinawhose government in 2010 announced a strategy to pursue malaria elimination in theChinese provincesthe required investment is a small proportion of public expenditure on health. In contrast, a similar program in Tanzania would [39] cost an estimated one-fifth of the public health budget.