tropical diseases
Tropical diseases are infectious diseases that are prevalent in or unique to tropical and subtropical regions. These diseases are less prevalent in temperate climates, due in part to the occurrence of a cold season, which controls the insect population by forcing hibernation during the cold season.[1] Insects such as mosquitoes and flies are by far the most common disease carrier or "vector". These insects may carry a parasite, bacterium or virus that is infectious to humans and animals. Most often disease is transmitted by an insect "bite", which causes transmission of the infectious agent through subcutaneous blood exchange. Vaccines are not available for any of the diseases listed here.[2]
Some of the strategies for controlling tropical diseases include:
Draining wetlands to reduce insect populations
The application of insecticides (or to a lesser extent, perhaps insect repellents) to strategic surfaces such as: clothing, skin, buildings, insect habitats, and bed nets.
The use of a mosquito net over a bed (also known as a "bed net"), to reduce nighttime transmission, since tropical mosquitoes often feed only at night.
Use of water wells, and/or water filtration, water filters, or water treatment with water tablets to produce drinking water free of parasites.
Development and use of vaccines to promote disease immunity
Funding and subsidizing the use of medicinal treatments to treat disease after infection
Assisting with economic development in endemic regions. For example by providing microloans to enable investments in more efficient and productive agriculture. This in turn can help subsistence farming to become more profitable, and these profits can be used by local populations for disease prevention and treatment, with the added benefit of reducing the poverty rate.[3]
Human exploration of tropical rainforests and increased international air travel and other tourism to tropical regions has led to an increased incidence of such diseases.[citation needed]
Contents
[hide]
1 Diseases
2 Relation of climate to tropical diseases
3 References
4 Further reading
4.1 Books
4.2 Journals
4.3 Websites
5 See also
6 External links
[edit] Diseases
In 1975 the United Nations Children's Fund, the United Nations Development Programme, the World Bank and the World Health Organization established the Special Programme for Research and Training in Tropical Diseases (TDR) to focus on neglected infectious diseases which disproportionately affect poor and marginalized populations in developing regions of Africa, Asia, Central America and South America. The current TDR disease portfolio includes the following ten entries:[4]
Malaria
Caused by a Protozoan parasites transmitted by Anopheles mosquitoes. It infects 300-500 million people each year, killing more than 1 million.[5]
African trypanosomiasis
or sleeping sickness, is a parasitic disease, caused by protozoa and transmitted by the tsetse fly
Dengue fever
a virus transmitted by mosquitoes
Leishmaniasis
caused by protozoan parasites, and transmitted by the bite of certain species of sand fly.
Schistosomiasis
also known as snail fever, is a parasitic disease caused by several species of flatworm in areas with freshwater snails, which may carry the parasite. The most common form of transmission is by wading or swimming in lakes, ponds and other bodies of water containing the snails and the parasite. More than 200 million people worldwide are infected by schistosomiasis.[6]
Tuberculosis†
(abbreviated as TB), is a bacterial infection of the lungs or other tissues, which is highly prevalent in the world, with mortality over 50% if untreated. It is a communicable disease, transmitted by aerosol expectorant from a cough, sneeze, speak, kiss, or spit. Over one-third of the world's population has been infected by the TB bacterium.[7]
Chagas disease
(also called American trypanosomiasis) is a parasitic disease which occurs in the Americas, particularly in South America. Its pathogenic agent is a flagellate protozoan named Trypanosoma cruzi, which is transmitted mostly by blood-sucking assassin bugs, however other methods of transmission are possible, such as ingestion of food contaminated with parasites, blood transfusion and fetal transmission. Between 16 and 18 million people are currently infected.[8]
Leprosy†
(or Hansen's disease) is a chronic infectious disease caused by a bacterium. Leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external symptom.[9] Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs, and eyes. Contrary to popular conception, leprosy does not cause body parts to simply fall off, and it differs from tzaraath, the malady described in the Hebrew scriptures and previously translated into English as leprosy.[10]
Worldwide, two to three million people are estimated to be permanently disabled because of Hansen's disease.[11] India has the greatest number of cases, with Brazil second and Myanmar third.[11]
The exact mechanism of transmission of leprosy is not known: prolonged close contact and transmission by nasal droplet have both been proposed.[12] It is treated with multidrug therapy (MDT).
incidence is spread throughout the world, and fluctuates between 640,000 - 767,000 new cases detected per year. It is endemic to 91 countries.
According to the WHO, new cases detected worldwide decreased by approximately 20% per year from 2001 to 2004. The global registered prevalence of HD was 286,063 cases; 407,791 new cases were detected during 2004.
Lymphatic filariasis
is a parasitic disease caused by thread-like parasitic filarial worms called nematode worms, all transmitted by mosquitoes. Loa loa is another filarial parasite transmitted by the deer fly. 120 million people are infected worldwide. It is carried by over half the population in the most severe endemic areas. [13]
The most noticeable symptom is elephantiasis: a thickening of the skin and underlying tissues.
Onchocerciasis
(pronounced [?n.k??.s??'ka??.s?s]) or river blindness is the world's second leading infectious cause of blindness. It is caused by Onchocerca volvulus, a parasitic worm.[14] It is transmitted through the bite of a black fly. The worms spread throughout the body, and when they die, they cause intense itching and a strong immune system response that can destroy nearby tissue, such as the eye.[15]
About 18 million people are currently infected with this parasite. Approximately 300,000 have been irreversibly blinded by it.[16]
Trachoma
is an infectious eye disease, and the leading cause of the world's infectious blindness.[17] Globally, 84 million people suffer from active infection and nearly 8 million people are visually impaired as a result of this disease.[18]
† Although leprosy and tuberculosis are not exclusively tropical diseases, their high incidence in the tropics justifies their inclusion.
Additional neglected tropical diseases include:[19]
Ascariasis
Trichuriasis
Hookworm
Human African trypanosomiasis
Dracunculiasis
Buruli ulcer
Treponematoses
Leptospirosis
Strongyloidiasis
Foodborne trematodiases
Neurocysticercosis
Scabies
Some tropical diseases are very rare, but may occur in sudden epidemics, such as the Ebola hemorrhagic fever, Lassa fever and the Marburg virus. There are hundreds of different tropical diseases which are less known or rarer, but that, nonetheless, have importance for public health.
[edit] Relation of climate to tropical diseases
The called "exotic" diseases in the tropics has long been noted both by travelers, explorers, etc., as well as by physicians. One obvious reason is that the hot climate present during all the year and the larger volume of rains directly affect the formation of breeding grounds, the larger number and variety of natural reservoirs and animal diseases that can be transmitted to humans (zoonosis), the largest number of possible insect vectors of diseases. It is possible also that higher temperatures may favor the replication of pathogenic agents both inside and outside biological organisms. Socio-economic factors may be also in operation, since most of the poorest nations of the world are in the tropics. Tropical countries like Brazil, which have improved their socio-economic situation and invested in hygiene, public health and the combat of transmissible diseases have achieved dramatic results in relation to the elimination or decrease of many endemic tropical diseases in their territory.[citation needed]
Climate change, and global warming caused by the greenhouse effect, and the resulting increase in global temperatures, are causing tropical diseases and vectors to spread to higher altitudes in mountainous regions, and to higher latitudes that were previously spared, such as the Southern United States, the Mediterranean area, etc.[20][21]
[edit] References
1.^ "Guns, Germs, and Steel" by Jared Diamond
2.^ See the Wikipedia articles for the respective diseases
3.^ Jeffrey Sachs
4.^ "Disease portfolio". Special Programme for Research and Training in Tropical Diseases. Retrieved on 2008-01-21.
5.^ Frequently Asked Questions | CDC Malaria
6.^ WHO | Schistosomiasis
7.^ World Health Organization (WHO). Tuberculosis Fact sheet N°104 - Global and regional incidence. March 2006, Retrieved on 6 October 2006.
8.^ Chagas Disease After Organ Transplantation --- United States, 2001
9.^ Kenneth J. Ryan and C. George Ray, Sherris Medical Microbiology Fourth Edition McGraw Hill 2004.
10.^ Leviticus 13:59, Artscroll Tanakh and Metsudah Chumash translations, 1996 and 1994, respectively.
11.^ a b WHO (1995). "Leprosy disabilities: magnitude of the problem". Weekly Epidemiological Record 70 (38): 269–75. PMID 7577430.
12.^ Reich CV (1987). "Leprosy: cause, transmission, and a new theory of pathogenesis". Rev. Infect. Dis. 9 (3): 590–4. PMID 3299638.
13.^ Aupali T, Ismid IS, Wibowo H, et al. (2006). "Estimation of the prevalence of lymphatic filariasis by a pool screen PCR assay using blood spots collected on filter paper". Tran R Soc Trop Med Hyg 100 (8): 753–9. doi:10.1016/j.trstmh.2005.10.005.
14.^ http://www.worldbank.org/afr/gper/disease.htm The World Bank | Global Partnership to Eliminate Riverblindness. Accessed November 04, 2007.
15.^ "Causes of river blindness". Retrieved on 2008-01-28.
16.^ "What is river blindness?". Retrieved on 2008-01-28.
17.^ About Neglected Tropical Diseases (NTDs)
18.^ WHO | Trachoma
19.^ Hotez, P. J. (September 2007). "Control of Neglected Tropical Diseases". The New England Journal of Medicine 357 (10): 1018–1027. doi:10.1056/NEJMra064142. PMID 17804846. 17804846. Retrieved on 2008-01-21.
20.^ Climate change brings malaria back to Italy The Guardian 6 January 2007
21.^ BBC Climate link to African malaria 20 March 2006
[edit] Further reading
[edit] Books
Manson's Tropical Diseases
Mandell's Principles and Practice of Infectious Diseases or this site
[edit] Journals
American Journal of Tropical Medicine and Hygiene
Japanese Journal of Tropical Medicine and Hygiene
Tropical Medicine and International Health
The Southeast Asian Journal of Tropical Medicine and Public Health
Revista do Instituto de Medicina Tropical de São Paulo
Revista da Sociedade Brasileira de Medicina Tropical
Journal of Venomous Animals and Toxins including Tropical Diseases
http://en.wikipedia.org/wiki/Malaria
Malaria
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Malaria
Classification and external resources
Plasmodium falciparum ring-forms and gametocytes in human blood.
ICD-10
B50.
ICD-9
084
OMIM
248310
DiseasesDB
7728
MedlinePlus
000621
eMedicine
med/1385 emerg/305 ped/1357
MeSH
C03.752.250.552
Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 515 million cases of malaria, killing between one and three million people, the majority of whom are young children in Sub-Saharan Africa.[1] Malaria is commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development.
Malaria is one of the most common infectious diseases and an enormous public health problem. The disease is caused by protozoan parasites of the genus Plasmodium. Only four types of the plasmodium parasite can infect humans; the most serious forms of the disease are caused by Plasmodium falciparum and Plasmodium vivax, but other related species (Plasmodium ovale, Plasmodium malariae) can also affect humans. This group of human-pathogenic Plasmodium species is usually referred to as malaria parasites.
Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within red blood cells, causing symptoms that include symptoms of anemia (light headedness, shortness of breath, tachycardia etc.), as well as other general symptoms such as fever, chills, nausea, flu-like illness, and in severe cases, coma and death. Malaria transmission can be reduced by preventing mosquito bites with mosquito nets and insect repellents, or by mosquito control measures such as spraying insecticides inside houses and draining standing water where mosquitoes lay their eggs.
Although some are under development, no vaccine is currently available for malaria; preventative drugs must be taken continuously to reduce the risk of infection. These prophylactic drug treatments are often too expensive for most people living in endemic areas. Most adults from endemic areas have a degree of long-term infection, which tends to recur and also possess partial immunity (resistance); the resistance reduces with time and such adults may become susceptible to severe malaria if they have spent a significant amount of time in non-endemic areas. They are strongly recommended to take full precautions if they return to an endemic area. Malaria infections are treated through the use of antimalarial drugs, such as quinine or artemisinin derivatives, although drug resistance is increasingly common.
Contents
[hide]
1 History
2 Distribution and impact
2.1 Socio-economic effects
3 Symptoms
4 Causes
4.1 Malaria parasites
5 Mosquito vectors and the Plasmodium life cycle
6 Pathogenesis
7 Evolutionary pressure of malaria on human genes
7.1 Sickle-cell disease
7.2 Thalassaemias
7.3 Duffy antigens
7.4 G6PD
7.5 HLA and interleukin-4
8 Diagnosis
8.1 Symptomatic diagnosis
8.2 Microscopic examination of blood films
8.3 Field tests
8.4 Molecular methods
8.5 Laboratory tests
9 Treatment
9.1 Antimalarial drugs
9.2 Counterfeit drugs
10 Prevention and disease control
10.1 Vector control
10.2 Prophylactic drugs
10.3 Indoor residual spraying
10.4 Mosquito nets and bedclothes
10.5 Vaccination
10.6 Other methods
11 See also
12 References
13 External links
History
Further information: History of malaria
Charles Louis Alphonse Laveran
Malaria has infected humans for over 50,000 years, and may have been a human pathogen for the entire history of our species.[2] Indeed, close relatives of the human malaria parasites remain common in chimpanzees, our closest relatives.[3] References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China.[4] The term malaria originates from Medieval Italian: mala aria — "bad air"; and the disease was formerly called ague or marsh fever due to its association with swamps.
Scientific studies on malaria made their first significant advance in 1880, when a French army doctor working in the military hospital of Constantine in Algeria named Charles Louis Alphonse Laveran observed parasites for the first time, inside the red blood cells of people suffering from malaria. He therefore proposed that malaria was caused by this protozoan, the first time protozoa were identified as causing disease.[5] For this and later discoveries, he was awarded the 1907 Nobel Prize for Physiology or Medicine. The protozoan was called Plasmodium by the Italian scientists Ettore Marchiafava and Angelo Celli.[6] A year later, Carlos Finlay, a Cuban doctor treating patients with yellow fever in Havana, provided strong evidence that mosquitoes were transmitting disease to and from humans.[7] This work followed earlier suggestions by Josiah C. Nott,[8] and work by Patrick Manson on the transmission of filariasis.[9]
However, it was Britain's Sir Ronald Ross working in the Presidency General Hospital in Calcutta who finally proved in 1898 that malaria is transmitted by mosquitoes. He did this by showing that certain mosquito species transmit malaria to birds and isolating malaria parasites from the salivary glands of mosquitoes that had fed on infected birds.[10] For this work Ross received the 1902 Nobel Prize in Medicine. After resigning from the Indian Medical Service, Ross worked at the newly-established Liverpool School of Tropical Medicine and directed malaria-control efforts in Egypt, Panama, Greece and Mauritius.[11] The findings of Finlay and Ross were later confirmed by a medical board headed by Walter Reed in 1900, and its recommendations implemented by William C. Gorgas in the health measures undertaken during construction of the Panama Canal. This public-health work saved the lives of thousands of workers and helped develop the methods used in future public-health campaigns against this disease.
The first effective treatment for malaria was the bark of cinchona tree, which contains quinine. This tree grows on the slopes of the Andes, mainly in Peru. This natural product was used by the inhabitants of Peru to control malaria, and the Jesuits introduced this practice to Europe during the 1640s where it was rapidly accepted.[12] However, it was not until 1820 that the active ingredient quinine was extracted from the bark, isolated and named by the French chemists Pierre Joseph Pelletier and Joseph Bienaimé Caventou.[13]
In the early twentieth century, before antibiotics, patients with syphilis were intentionally infected with malaria to create a fever, following the work of Julius Wagner-Jauregg. By accurately controlling the fever with quinine, the effects of both syphilis and malaria could be minimized. Although some patients died from malaria, this was preferable to the almost-certain death from syphilis.[14]
Although the blood stage and mosquito stages of the malaria life cycle were identified in the 19th and early 20th centuries, it was not until the 1980s that the latent liver form of the parasite was observed.[15][16] The discovery of this latent form of the parasite finally explained why people could appear to be cured of malaria but still relapse years after the parasite had disappeared from their bloodstreams.
Distribution and impact
Further information: Diseases of poverty, Tropical disease
Areas of the world where malaria is endemic as of 2003 (coloured yellow).[17]
Malaria causes about 400–900 million cases of fever and approximately one to three million deaths annually[18][19] — this represents at least one death every 30 seconds. The vast majority of cases occur in children under the age of 5 years;[20] pregnant women are also especially vulnerable. Despite efforts to reduce transmission and increase treatment, there has been little change in which areas are at risk of this disease since 1992.[21] Indeed, if the prevalence of malaria stays on its present upwards course, the death rate could double in the next twenty years.[18] Precise statistics are unknown because many cases occur in rural areas where people do not have access to hospitals or the means to afford health care. Consequently, the majority of cases are undocumented.[18]
Although co-infection with HIV and malaria does cause increased mortality, this is less of a problem than with HIV/tuberculosis co-infection, due to the two diseases usually attacking different age-ranges, with malaria being most common in the young and active tuberculosis most common in the old.[22] Although HIV/malaria co-infection produces less severe symptoms than the interaction between HIV and TB, HIV and malaria do contribute to each other's spread. This effect comes from malaria increasing viral load and HIV infection increasing a person's susceptibility to malaria infection.[23]
Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.[24] The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other.[25] In drier areas, outbreaks of malaria can be predicted with reasonable accuracy by mapping rainfall.[26] Malaria is more common in rural areas than in cities; this is in contrast to dengue fever where urban areas present the greater risk.[27] For example, the cities of Vietnam, Laos and Cambodia are essentially malaria-free, but the disease is present in many rural regions.[28] By contrast, in Africa malaria is present in both rural and urban areas, though the risk is lower in the larger cities.[29] The global endemic levels of malaria have not been mapped since the 1960s. However, the Wellcome Trust, UK, has funded the Malaria Atlas Project[30] to rectify this, providing a more contemporary and robust means with which to assess current and future malaria disease burden.
Socio-economic effects
Malaria is not just a disease commonly associated with poverty, but is also a cause of poverty and a major hindrance to economic development. The disease has been associated with major negative economic effects on regions where it is widespread. A comparison of average per capita GDP in 1995, adjusted to give parity of purchasing power, between malarious and non-malarious countries demonstrates a fivefold difference ($1,526 USD versus $8,268 USD). Moreover, in countries where malaria is common, average per capita GDP has risen (between 1965 and 1990) only 0.4% per year, compared to 2.4% per year in other countries.[31] However, correlation does not demonstrate causation, and the prevalence is at least partly because these regions do not have the financial capacities to prevent malaria. In its entirety, the economic impact of malaria has been estimated to cost Africa $12 billion USD every year. The economic impact includes costs of health care, working days lost due to sickness, days lost in education, decreased productivity due to brain damage from cerebral malaria, and loss of investment and tourism.[20] In some countries with a heavy malaria burden, the disease may account for as much as 40% of public health expenditure, 30-50% of inpatient admissions, and up to 50% of outpatient visits.[32]
Symptoms
Symptoms of malaria include fever, shivering, arthralgia (joint pain), vomiting, anemia (caused by hemolysis), hemoglobinuria, and convulsions. There may be a feeling of tingling in the skin, particularly with malaria caused by P. falciparum.[citation needed] The classical symptom of malaria is cyclical occurrence of sudden coldness followed by rigor and then fever and sweating lasting four to six hours, occurring every two days in P. vivax and P. ovale infections, while every three for P. malariae.[33] P. falciparum can have recurrent fever every 36-48 hours or a less pronounced and almost continuous fever. For reasons that are poorly understood, but which may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage.[34] Malaria has been found to cause cognitive impairments, especially in children. It causes widespread anemia during a period of rapid brain development and also direct brain damage. This neurologic damage results from cerebral malaria to which children are more vulnerable.[35]
Severe malaria is almost exclusively caused by P. falciparum infection and usually arises 6-14 days after infection.[36] Consequences of severe malaria include coma and death if untreated—young 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 may cause blackwater fever, where hemoglobin from lysed red blood cells leaks into the urine. Severe malaria can progress extremely rapidly and cause death within hours or days.[36] In the most severe cases of the disease fatality rates can exceed 20%, even with intensive care and treatment.[37] In endemic areas, treatment is often less satisfactory and the overall fatality rate for all cases of malaria can be as high as one in ten.[38] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria.[39]
Chronic malaria is seen in both P. vivax and P. ovale, but not in P. falciparum. Here, the disease can relapse months or years after exposure, due to the presence of latent parasites in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can therefore be deceptive. The longest incubation period reported for a P. vivax infection is 30 years.[36] Approximately one in five of P. vivax malaria cases in temperate areas involve overwintering by hypnozoites (i.e., relapses begin the year after the mosquito bite).[40]
Causes
A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph.
Malaria parasites
Malaria is caused by protozoan parasites of the genus Plasmodium (phylum Apicomplexa). In humans malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. P. falciparum is the most common cause of infection and is responsible for about 80% of all malaria cases, and is also responsible for about 90% of the deaths from malaria.[41] Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.[42] There have been documented human infections with several simian species of malaria, namely P. knowlesi, P. inui, P. cynomolgi,[43] P. simiovale, P. brazilianum, P. schwetzi and P. simium; however, with the exception of P. knowlesi, these are mostly of limited public health importance. Although avian malaria can kill chickens and turkeys, this disease does not cause serious economic losses to poultry farmers.[44] However, since being accidentally introduced by humans it has decimated the endemic birds of Hawaii, which evolved in its absence and lack any resistance to it.[45]
Mosquito vectors and the Plasmodium life cycle
The parasite's primary (definitive) hosts and transmission vectors are female mosquitoes of the Anopheles genus. Young mosquitoes first ingest the malaria parasite by feeding on an infected human carrier and the infected Anopheles mosquitoes carry Plasmodium sporozoites in their salivary glands. A mosquito becomes infected when it takes a blood meal from an infected human. Once ingested, the parasite gametocytes taken up in the blood will further differentiate into male or female gametes and then fuse in the mosquito 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. This type of transmission is occasionally referred to as anterior station transfer.[46] The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal.
Only female mosquitoes feed on blood, thus males do not transmit the disease. The females of the Anopheles genus of mosquito prefer to feed at night. They usually start searching for a meal at dusk, and will continue throughout the night until taking a meal. Malaria parasites can also be transmitted by blood transfusions, although this is rare.[47]
Pathogenesis
The life cycle of malaria parasites in the human body. A mosquito infects a pregnant woman, first in the liver and then in the bloodstream. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells (erythrocytes), where they develop into ring forms, then trophozoites (a feeding stage), then multinucleated schizonts (a reproduction stage), then merozoites again. The merozoites rupture the blood cells and return to the bloodstream to infect more blood cells. Only the ring forms circulate in the bloodstream; the other red blood cells stick (adhere) to the walls (endothelium) of small blood vessels (venules), preventing the infected red blood cells from traveling to the spleen and being destroyed.
Malaria in humans develops via two phases: an exoerythrocytic (exo=outside; erythrocutic=red blood cell), i.e., mainly in the liver (hepatic), and an erythrocytic phase. 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. Within 30 minutes of being introduced into the human host, they infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. Once 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, thus beginning the erythrocytic stage of the life cycle.[48] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell.[49]
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 simultaneous waves of merozoites escaping and infecting red blood cells.
Some P. vivax and P. ovale sporozoites do not immediately develop into exoerythrocytic-phase merozoites, but instead produce hypnozoites that remain dormant for periods ranging from several months (6–12 months is typical) to as long as three years. After a period of dormancy, they reactivate and produce merozoites. Hypnozoites are responsible for long incubation and late relapses in these two species of malaria.[50]
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 sequestering the parasite from passage through the general circulation and the spleen.[51] This "stickiness" is the main factor giving rise to hemorrhagic complications of malaria. High endothelial venules (the smallest branches of the circulatory system) can be blocked by the attachment of masses of these infected red blood cells. The blockage of these vessels causes symptoms such as in placental and cerebral malaria. In cerebral malaria the sequestrated red blood cells can breach the blood brain barrier possibly leading to coma.[52]
Although the red blood cell surface adhesive proteins (called PfEMP1, for Plasmodium 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 perhaps limitless versions within parasite populations.[51] Like a thief changing disguises or a spy with multiple passports, the parasite switches between a broad repertoire of PfEMP1 surface proteins, thus staying one step 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, thereby defining the mosquito as the definitive host of the disease. New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes,[53] and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight,[54] particularly in P. falciparum infection, but also in other species infection, such as P. vivax.[55]
Evolutionary pressure of malaria on human genes
Further information: Evolution, Natural selection
Malaria is thought to have been the greatest selective pressure on the human genome in recent history.[56] This is due to the high levels of mortality and morbidity caused by malaria, especially the P. falciparum species.
Sickle-cell disease
Distribution of the sickle cell trait.
Distribution of malaria.
The best-studied influence of the malaria parasite upon the human genome is the blood disease, sickle-cell disease. In sickle-cell disease, there is a mutation in the HBB gene, which encodes the beta globin subunit of haemoglobin. The normal allele encodes a glutamate at position six of the beta globin protein, while the sickle-cell allele encodes a valine. This change from a hydrophilic to a hydrophobic amino acid encourages binding between haemoglobin molecules, with polymerization of haemoglobin deforming red blood cells into a "sickle" shape. Such deformed cells are cleared rapidly from the blood, mainly in the spleen, for destruction and recycling.
In the merozoite stage of its life cycle the malaria parasite lives inside red blood cells, and its metabolism changes the internal chemistry of the red blood cell. Infected cells normally survive until the parasite reproduces, but if the red cell contains a mixture of sickle and normal haemoglobin, it is likely to become deformed and be destroyed before the daughter parasites emerge. Thus, individuals heterozygous for the mutated allele, known as sickle-cell trait, may have a low and usually unimportant level of anaemia, but also have a greatly reduced chance of serious malaria infection. This is a classic example of heterozygote advantage.
Individuals homozygous for the mutation have full sickle-cell disease and in traditional societies rarely live beyond adolescence. However, in populations where malaria is endemic, the frequency of sickle-cell genes is around 10%. The existence of four haplotypes of sickle-type hemoglobin suggests that this mutation has emerged independently at least four times in malaria-endemic areas, further demonstrating its evolutionary advantage in such affected regions. There are also other mutations of the HBB gene that produce haemoglobin molecules capable of conferring similar resistance to malaria infection. These mutations produce haemoglobin types HbE and HbC which are common in Southeast Asia and Western Africa, respectively.
Thalassaemias
Another well documented set of mutations found in the human genome associated with malaria are those involved in causing blood disorders known as thalassaemias. Studies in Sardinia and Papua New Guinea have found that the gene frequency of ß-thalassaemias is related to the level of malarial endemicity in a given population. A study on more than 500 children in Liberia found that those with ß-thalassaemia had a 50% decreased chance of getting clinical malaria. Similar studies have found links between gene frequency and malaria endemicity in the a+ form of a-thalassaemia. Presumably these genes have also been selected in the course of human evolution.
Duffy antigens
The Duffy antigens are antigens expressed on red blood cells and other cells in the body acting as a chemokine receptor. The expression of Duffy antigens on blood cells is encoded by Fy genes (Fya, Fyb, Fyc etc.). Plasmodium vivax malaria uses the Duffy antigen to enter blood cells. However, it is possible to express no Duffy antigen on red blood cells (Fy-/Fy-). This genotype confers complete resistance to P. vivax infection. The genotype is very rare in European, Asian and American populations, but is found in almost all of the indigenous population of West and Central Africa.[57] This is thought to be due to very high exposure to P. vivax in Africa in the last few thousand years.
G6PD
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme which normally protects from the effects of oxidative stress in red blood cells. However, a genetic deficiency in this enzyme results in increased protection against severe malaria.
HLA and interleukin-4
HLA-B53 is associated with low risk of severe malaria. This MHC class I molecule presents liver stage and sporozoite antigens to T-Cells. Interleukin-4, encoded by IL4, is produced by activated T cells and promotes proliferation and differentiation of antibody-producing B cells. A study of the Fulani of Burkina Faso, who have both fewer malaria attacks and higher levels of antimalarial antibodies than do neighboring ethnic groups, found that the IL4-524 T allele was associated with elevated antibody levels against malaria antigens, which raises the possibility that this might be a factor in increased resistance to malaria.[58]
Diagnosis
Further information: Blood film
Blood smear from a P. falciparum culture (K1 strain). Several red blood cells have ring stages inside them. Close to the center there is a schizont and on the left a trophozoite.
Severe malaria is commonly misdiagnosed in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. Recent investigations suggest that malarial retinopathy is better (collective sensitivity of 95% and specificity of 90%) than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma.[59]
Symptomatic diagnosis
Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).[60]
Microscopic examination of blood films
For more details on individual parasites, see P. falciparum, P. vivax, P. ovale, P. malariae.
The most economic, preferred, and reliable diagnosis of malaria is microscopic examination of blood films because each of the four major parasite species has distinguishing characteristics. Two sorts of blood film are traditionally used. Thin films are similar to usual blood films and allow species identification because the parasite's appearance is best preserved in this preparation. Thick films allow the microscopist to screen a larger volume of blood and are about eleven times more sensitive than the thin film, so picking up low levels of infection is easier on the thick film, but the appearance of the parasite is much more distorted and therefore distinguishing between the different species can be much more difficult. With the pros and cons of both thick and thin smears taken into consideration, it is imperative to utilize both smears while attempting to make a definitive diagnosis.[61]
From the thick film, an experienced microscopist can detect parasite levels (or parasitemia) down to as low as 0.0000001% of red blood cells. Diagnosis of species can be difficult because the early trophozoites ("ring form") of all four species look identical and it is never possible to diagnose species on the basis of a single ring form; species identification is always based on several trophozoites.
Field tests
In areas where microscopy is not available, or where laboratory staff are not experienced at malaria diagnosis, there are antigen detection tests that require only a drop of blood.[62] Immunochromatographic tests (also called: Malaria Rapid Diagnostic Tests, Antigen-Capture Assay or "Dipsticks") have been developed, distributed and fieldtested. These tests use finger-stick or venous blood, the completed test takes a total of 15-20 minutes, and a laboratory is not needed. The threshold of detection by these rapid diagnostic tests is in the range of 100 parasites/µl of blood compared to 5 by thick film microscopy. The first rapid diagnostic tests were using P. falciparum glutamate dehydrogenase as antigen [63]. PGluDH was soon replaced by P.falciparum lactate dehydrogenase, a 33 kDa oxidoreductase [EC 1.1.1.27]. It is the last enzyme of the glycolytic pathway, essential for ATP generation and one of the most abundant enzymes expressed by P.falciparum. PLDH does not persist in the blood but clears about the same time as the parasites following successful treatment. The lack of antigen persistence after treatment makes the pLDH test useful in predicting treatment failure. In this respect, pLDH is similar to pGluDH. The OptiMAL-IT assay can distinguish between P. falciparum and P. vivax because of antigenic differences between their pLDH isoenzymes. OptiMAL-IT will reliably detect falciparum down to 0.01% parasitemia and non-falciparum down to 0.1%. Paracheck-Pf will detect parasitemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria. Parasite nucleic acids are detected using polymerase chain reaction. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field. Areas that cannot afford even simple laboratory diagnostic tests often use only a history of subjective fever as the indication to treat for malaria. Using Giemsa-stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors (rectal temperature, nailbed pallor, and splenomegaly) were used as treatment indications, rather than the current national policy of using only a history of subjective fevers (sensitivity increased from 21% to 41%).[64]
Molecular methods
Molecular methods are available in some clinical laboratories and rapid real-time assays (for example, QT-NASBA based on the polymerase chain reaction)[65] are being developed with the hope of being able to deploy them in endemic areas.
Laboratory tests
OptiMAL-IT will reliably detect falciparum down to 0.01% parasitemia and non-falciparum down to 0.1%. Paracheck-Pf will detect parasitemias down to 0.002% but will not distinguish between falciparum and non-falciparum malaria. Parasite nucleic acids are detected using polymerase chain reaction. This technique is more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. Moreover, levels of parasitemia are not necessarily correlative with the progression of disease, particularly when the parasite is able to adhere to blood vessel walls. Therefore more sensitive, low-tech diagnosis tools need to be developed in order to detect low levels of parasitaemia in the field. [66]
Treatment
Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete recovery.[67]
Antimalarial drugs
Further information: Antimalarial drugs
There are several families of drugs used to treat malaria. Chloroquine is very cheap and, until recently, was very effective, which made it the antimalarial drug of choice for many years in most parts of the world. However, resistance of Plasmodium falciparum to chloroquine has spread recently from Asia to Africa, making the drug ineffective against the most dangerous Plasmodium strain in many affected regions of the world. In those areas where chloroquine is still effective it remains the first choice. Unfortunately, chloroquine-resistance is associated with reduced sensitivity to other drugs such as quinine and amodiaquine.[68]
There are several other substances which are used for treatment and, partially, for prevention (prophylaxis). Many drugs may be used for both purposes; larger doses are used to treat cases of malaria. Their deployment depends mainly on the frequency of resistant parasites in the area where the drug is used. One drug currently being investigated for possible use as an anti-malarial, especially for treatment of drug-resistant strains, is the beta blocker propranolol. Propranolol has been shown to block both Plasmodium's ability to enter red blood cell and establish an infection, as well as parasite replication. A December 2006 study by Northwestern University researchers suggested that propranolol may reduce the dosages required for existing drugs to be effective against P. falciparum by 5- to 10-fold, suggesting a role in combination therapies.[69]
Currently available anti-malarial drugs include:[70]
Artemether-lumefantrine (Therapy only, commercial names Coartem and Riamet)
Artesunate-amodiaquine (Therapy only)
Artesunate-mefloquine (Therapy only)
Artesunate-Sulfadoxine/pyrimethamine (Therapy only)
Atovaquone-proguanil, trade name Malarone (Therapy and prophylaxis)
Quinine (Therapy only)
Chloroquine (Therapy and prophylaxis; usefulness now reduced due to resistance)
Cotrifazid (Therapy and prophylaxis)
Doxycycline (Therapy and prophylaxis)
Mefloquine, trade name Lariam (Therapy and prophylaxis)
Primaquine (Therapy in P. vivax and P. ovale only; not for prophylaxis)
Proguanil (Prophylaxis only)
Sulfadoxine-pyrimethamine (Therapy; prophylaxis for semi-immune pregnant women in endemic countries as "Intermittent Preventive Treatment" - IPT)
Hydroxychloroquine, trade name Plaquenil (Therapy and prophylaxis)
The development of drugs was facilitated when Plasmodium falciparum was successfully cultured.[71] This allowed in vitro testing of new drug candidates.
Extracts of the plant Artemisia annua, containing the compound artemisinin or semi-synthetic derivatives (a substance unrelated to quinine), offer over 90% efficacy rates, but their supply is not meeting demand.[72] One study in Rwanda showed that children with uncomplicated P. falciparum malaria demonstrated fewer clinical and parasitological failures on post-treatment day 28 when amodiaquine was combined with artesunate, rather than administered alone (OR = 0.34). However, increased resistance to amodiaquine during this study period was also noted.[73] Since 2001 the World Health Organization has recommended using artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria in areas experiencing resistance to older medications. The most recent WHO treatment guidelines for malaria recommend four different ACTs. While numerous countries, including most African nations, have adopted the change in their official malaria treatment policies, cost remains a major barrier to ACT implementation. Because ACTs cost up to twenty times as much as older medications, they remain unaffordable in many malaria-endemic countries. The molecular target of artemisinin is controversial, although recent studies suggest that SERCA, a calcium pump in the endoplasmic reticulum may be associated with artemisinin resistance.[74] Malaria parasites can develop resistance to artemisinin and resistance can be produced by mutation of SERCA.[75] However, other studies suggest the mitochondrion is the major target for artemisinin and its analogs.[76]
In February 2002, the journal Science and other press outlets[77] announced progress on a new treatment for infected individuals. A team of French and South African researchers had identified a new drug they were calling "G25".[78] It cured malaria in test primates by blocking the ability of the parasite to copy itself within the red blood cells of its victims. In 2005 the same team of researchers published their research on achieving an oral form, which they refer to as "TE3" or "te3".[79] As of early 2006, there is no information in the mainstream press as to when this family of drugs will become commercially available.
In 1996, Professor Geoff McFadden stumbled upon the work of British biologist Ian Wilson, who had discovered that the plasmodia responsible for causing malaria retained parts of chloroplasts,[80] an organelle usually found in plants, complete with their own functioning genomes. This led Professor McFadden to the realisation that any number of herbicides may in fact be successful in the fight against malaria, and so he set about trialing large numbers of them, and enjoyed a 75% success rate.
These "apicoplasts" are thought to have originated through the endosymbiosis of algae[81] and play a crucial role in fatty acid bio-synthesis in plasmodia.[82] To date, 466 proteins have been found to be produced by apicoplasts[83] and these are now being looked at as possible targets for novel anti-malarial drugs.
Although effective anti-malarial drugs are on the market, the disease remains a threat to people living in endemic areas who have no proper and prompt access to effective drugs. Access to pharmacies and health facilities, as well as drug costs, are major obstacles. Médecins Sans Frontières estimates that the cost of treating a malaria-infected person in an endemic country was between US$0.25 and $2.40 per dose in 2002.[84]
Counterfeit drugs
Sophisticated counterfeits have been found in several Asian countries such as Cambodia[85], China,[86], Indonesia, Laos, Thailand, Vietnam and are an important cause of avoidable death in these countries.[87] WHO have said that studies indicate that up to 40% of artesunate based malaria medications are counterfeit, especially in the Greater Mekong region and have established a rapid alert system to enable information about counterfeit drugs to be rapidly reported to the relevant authorities in participating countries.[88] There is no reliable way for doctors or lay people to detect counterfeit drugs without help from a laboratory. Companies are attempting to combat the persistence of counterfeit drugs by using new technology to provide security from source to distribution.
Prevention and disease control
Anopheles albimanus mosquito feeding on a human arm. This mosquito is a vector of malaria and mosquito control is a very effective way of reducing the incidence of malaria.
Methods used to prevent the spread of disease, or to protect individuals in areas where malaria is endemic, include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. The continued existence 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 sooner or later disappear from that area, as happened in North America, Europe and much of Middle East. However, unless the parasite is eliminated from the whole world, it could become re-established if conditions revert to a combination that favors the parasite's reproduction. Many countries are seeing an increasing number of imported malaria cases due to extensive travel and migration. (See Anopheles.)
There is currently no vaccine that will prevent malaria, but this is an active field of research.
Many researchers argue that prevention of malaria may be more cost-effective than treatment of the disease in the long run, but the capital costs required are out of reach of many of the world's poorest people. Economic adviser Jeffrey Sachs estimates that malaria can be controlled for US$3 billion in aid per year. It has been argued that, in order to meet the Millennium Development Goals, money should be redirected from HIV/AIDS treatment to malaria prevention, which for the same amount of money would provide greater benefit to African economies.[89]
Brazil, Eritrea, India, and Vietnam have, unlike many other developing nations, successfully reduced the malaria burden. Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing.[90]
Vector control
Further information: Mosquito control
Before DDT, malaria was successfully eradicated or controlled also in several tropical areas by removing or poisoning the breeding grounds of the mosquitoes or the aquatic habitats of the larva stages, for example by filling or applying oil to places with standing water. These methods have seen little application in Africa for more than half a century.[91]
Efforts to eradicate malaria by eliminating mosquitoes have been successful in some areas. Malaria was once common in the United States and southern Europe, but the draining of wetland breeding grounds and better sanitation, in conjunction with the monitoring and treatment of infected humans, eliminated it from affluent regions. In 2002, there were 1,059 cases of malaria reported in the US, including eight deaths. In five of those cases, the disease was contracted in the United States. Malaria was eliminated from the northern parts of the USA in the early twentieth century, and the use of the pesticide DDT eliminated it from the South by 1951. In the 1950s and 1960s, there was a major public health effort to eradicate malaria worldwide by selectively targeting mosquitoes in areas where malaria was rampant.[92] However, these efforts have so far failed to eradicate malaria in many parts of the developing world - the problem is most prevalent in Africa.
Sterile insect technique is emerging as a potential mosquito control method. Progress towards transgenic, or genetically modified, insects suggest that wild mosquito populations could be made malaria-resistant. Researchers at Imperial College London created the world's first transgenic malaria mosquito,[93] with the first plasmodium-resistant species announced by a team at Case Western Reserve University in Ohio in 2002.[94] Successful replacement of existent populations with genetically modified populations, relies upon a drive mechanism, such as transposable elements to allow for non-Mendelian inheritance of the gene of interest.
On December 21, 2007, a study published in PLoS Pathogens found that the hemolytic C-type lectin CEL-III from Cucumaria echinata, a sea cucumber found in the Bay of Bengal, impaired the development of the malaria parasite when produced by transgenic mosquitoes.[95][96] This could potentially be used one day to control malaria by using genetically modified mosquitoes refractory to the parasites, although the authors of the study recognize that there are numerous scientific and ethical problems to be overcome before such a control strategy could be implemented.
Prophylactic drugs
Main article: Malaria prophylaxis
Several drugs, most of which are also used for treatment of malaria, can be taken preventively. Generally, these drugs are taken daily or weekly, at a lower dose than would be used for treatment of a person who had actually contracted the disease. Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.
Quinine was used starting in the seventeenth century as a prophylactic against malaria. The development of more effective alternatives such as quinacrine, chloroquine, and primaquine in the twentieth century reduced the reliance on quinine. Today, quinine is still used to treat chloroquine resistant Plasmodium falciparum, as well as severe and cerebral stages of malaria, but is not generally used for prophylaxis. Of interesting historical note is the observation by Samuel Hahnemann in the late 18th century that over-dosing of quinine leads to a symptomatic state very similar to that of malaria itself. This lead Hahnemann to develop the medical Law of Similars, and the subsequent medical system of Homeopathy.
Modern drugs used preventively include mefloquine (Lariam), doxycycline (available generically), and the combination of atovaquone and proguanil hydrochloride (Malarone). The choice of which drug to use depends on which drugs the parasites in the area are resistant to, as well as side-effects and other considerations. The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards).
Indoor residual spraying
Indoor residual spraying (IRS) is the practice of spraying insecticides on the interior walls of homes in malaria effected areas. After feeding, many mosquito species rest on a nearby surface while digesting the bloodmeal, so if the walls of dwellings have been coated with insecticides, the resting mosquitos will be killed before they can bite another victim, transferring the malaria parasite.
The first and historically the most popular insecticide used for IRS is DDT. While it was initially used to exclusively to combat malaria, its use quickly spread to agriculture. In time, pest-control, rather than disease-control, came to dominate DDT use, and this large-scale agricultural use led to the evolution of resistant mosquitoes in many regions. During the 1960s, awareness of the negative consequences of its indiscriminate use increased ultimately leading to bans on agricultural applications of DDT in many countries in the 1970s.
Though DDT has never been banned for use in malaria control and there are several other insecticides suitable for IRS, some advocates have claimed that bans are responsible for tens of millions of deaths in tropical countries where DDT had once been effective in controlling malaria. Furthermore, most of the problems associated with DDT use stem specifically from its industrial-scale application in agriculture, rather than its use in public health.[97]
The World Health Organization (WHO) currently advises the use of 12 different insecticides in IRS operations. These include DDT and a series of alternative insecticides (such as the pyrethroids permethrin and deltamethrin) to both combat malaria in areas where mosquitoes are DDT-resistant, and to slow the evolution of resistance.[98] This public health use of small amounts of DDT is permitted under the Stockholm Convention on Persistent Organic Pollutants (POPs), which prohibits the agricultural use of DDT.[99] However, because of its legacy, many developed countries discourage DDT use even in small quantities.[100]
Mosquito nets and bedclothes
Mosquito nets help keep mosquitoes away from people, and thus greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier, so they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITN) are estimated to be twice as effective as untreated nets,[89] and offer greater than 70% protection compared with no net.[101] Since the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.
The distribution of mosquito nets impregnated with insecticide (often permethrin or deltamethrin) has been shown to be an extremely effective method of malaria prevention, and it is also one of the most cost-effective methods of prevention. These nets can often be obtained for around US$2.50 - $3.50 (2-3 euro) from the United Nations, the World Health Organization, and others.
For maximum effectiveness, the nets should be re-impregnated with insecticide every six months. This process poses a significant logistical problem in rural areas. New technologies like Olyset or DawaPlus allow for production of long-lasting insecticidal mosquito nets (LLINs), which release insecticide for approximately 5 years,[102] and cost about US$5.50. ITNs have the advantage of protecting people sleeping under the net and simultaneously killing mosquitoes that contact the net. This has the effect of killing the most dangerous mosquitoes. Some protection is also provided to others, including people sleeping in the same room but not under the net.
Unfortunately, the cost of treating malaria is high relative to income, and the illness results in lost wages. Consequently, the financial burden means that the cost of a mosquito net is often unaffordable to people in developing countries, especially for those most at risk. Only 1 out of 20 people in Africa own a bed net.[89] Although shipped into Africa mainly from Europe as free development help, the nets quickly become expensive trade goods. They are mainly used for fishing, and by combining hundreds of donated mosquito nets, whole river sections can be completely shut off, catching even the smallest fish.[103]
A study among Afghan refugees in Pakistan found that treating top-sheets and chaddars (head coverings) with permethrin has similar effectiveness to using a treated net, but is much cheaper.[104]
A new approach, announced in Science on June 10, 2005, uses spores of the fungus Beauveria bassiana, sprayed on walls and bed nets, to kill mosquitoes. While some mosquitoes have developed resistance to chemicals, they have not been found to develop a resistance to fungal infections.[105]
Vaccination
Further information: Malaria vaccine
Vaccines for malaria are under development, with no completely effective vaccine yet available. The first promising studies demonstrating the potential for a malaria vaccine were performed in 1967 by immunizing mice with live, radiation-attenuated sporozoites, providing protection to about 60% of the mice upon subsequent injection with normal, viable sporozoites.[106] Since the 1970s, there has been a considerable effort to develop similar vaccination strategies within humans. It was determined that an individual can be protected from a P. falciparum infection if they receive over 1000 bites from infected, irradiated mosquitoes.[107]
It has been generally accepted that it is impractical to provide at-risk individuals with this vaccination strategy, but that has been recently challenged with work being done by Dr. Stephen Hoffman of Sanaria, one of the key researchers who originally sequenced the genome of Plasmodium falciparum. His work most recently has revolved around solving the logistical problem of isolating and preparing the parasites equivalent to a 1000 irradiated mosquitoes for mass storage and inoculation of human beings. The company has recently received several multi-million dollar grants from the Bill & Melinda Gates Foundation and the U.S. government to begin early clinical studies in 2007 and 2008.[108] The Seattle Biomedical Research Institute (SBRI), funded by the Malaria Vaccine Initiative, assures potential volunteers that "the [2009] clinical trials won't be a life-threatening experience. While many volunteers [in Seattle] will actually contract malaria, the cloned strain used in the experiments can be quickly cured, and does not cause a recurring form of the disease." "Some participants will get experimental drugs or vaccines, while others will get placebo."[109]
Instead, much work has been performed to try and understand the immunological processes that provide protection after immunization with irradiated sporozoites. After the mouse vaccination study in 1967,[106] it was hypothesized that the injected sporozoites themselves were being recognized by the immune system, which was in turn creating antibodies against the parasite. It was determined that the immune system was creating antibodies against the circumsporozoite protein (CSP) which coated the sporozoite.[110] Moreover, antibodies against CSP prevented the sporozoite from invading hepatocytes.[111] CSP was therefore chosen as the most promising protein on which to develop a vaccine against the malaria sporozoite. It is for these historical reasons that vaccines based on CSP are the most numerous of all malaria vaccines.
Presently, there is a huge variety of vaccine candidates on the table. Pre-erythrocytic vaccines (vaccines that target the parasite before it reaches the blood), in particular vaccines based on CSP, make up the largest group of research for the malaria vaccine. Other vaccine candidates include: those that seek to induce immunity to the blood stages of the infection; those that seek to avoid more severe pathologies of malaria by preventing adherence of the parasite to blood venules and placenta; and transmission-blocking vaccines that would stop the development of the parasite in the mosquito right after the mosquito has taken a bloodmeal from an infected person.[112] It is hoped that the sequencing of the P. falciparum genome will provide targets for new drugs or vaccines.[113]
The first vaccine developed that has undergone field trials, is the SPf66, developed by Manuel Elkin Patarroyo in 1987. It presents a combination of antigens from the sporozoite (using CS repeats) and merozoite parasites. During phase I trials a 75% efficacy rate was demonstrated and the vaccine appeared to be well tolerated by subjects and immunogenic. The phase IIb and III trials were less promising, with the efficacy falling to between 38.8% and 60.2%. A trial was carried out in Tanzania in 1993 demonstrating the efficacy to be 31% after a years follow up, however the most recent (though controversial) study in the Gambia did not show any effect. Despite the relatively long trial periods and the number of studies carried out, it is still not known how the SPf66 vaccine confers immunity; it therefore remains an unlikely solution to malaria. The CSP was the next vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporoziote protein, but additionally has the recombinant (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.
The efficacy of Patarroyo's vaccine has been disputed with some US scientists concluding in The Lancet (1997) that "the vaccine was not effective and should be dropped" while the Colombian accused them of "arrogance" putting down their assertions to the fact that he came from a developing country.
The RTS,S/AS02A vaccine is the candidate furthest along in vaccine trials. It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation), the pharmaceutical company, GlaxoSmithKline, and the Walter Reed Army Institute of Research[114] In the vaccine, a portion of CSP has been fused to the immunogenic "S antigen" of the hepatitis B virus; this recombinant protein is injected alongside the potent AS02A adjuvant.[112] In October 2004, the RTS,S/AS02A researchers announced results of a Phase IIb trial, indicating the vaccine reduced infection risk by approximately 30% and severity of infection by over 50%. The study looked at over 2,000 Mozambican children.[115] More recent testing of the RTS,S/AS02A vaccine has focused on the safety and efficacy of administering it earlier in infancy: In October 2007, the researchers announced results of a phase I/IIb trial conducted on 214 Mozambican infants between the ages of 10 and 18 months in which the full three-dose course of the vaccine led to a 62% reduction of infection with no serious side-effects save some pain at the point of injection.[116] Further research will delay this vaccine from commercial release until around 2011.[117]
Other methods
Education in recognising the symptoms of malaria has reduced the number of cases in some areas of the developing world by as much as 20%. Recognising the disease in the early stages can also stop the disease from becoming a killer. Education can also inform people to cover over areas of stagnant, still water eg Water Tanks which are ideal breeding grounds for the parasite and mosquito thus, cutting down the risk of the transmission between people. This is most put in practice in urban areas where there is large centres of population in a confined space and transmission would be most likely in these areas.
The Malaria Control Project is currently using downtime computing power donated by individual volunteers around the world (see Volunteer computing and BOINC) to simulate models of the health effects and transmission dynamics in order to find the best method or combination of methods for malaria control. This modeling is extremely computer intensive due to the simulations of large human populations with a vast range of parameters related to biological and social factors that influence the spread of the disease. It is expected to take a few months using volunteered computing power compared to the 40 years it would have taken with the current resources available to the scientists who developed the program.[118]
An example of the importance of computer modelling in planning malaria eradication programs is shown in the paper by Águas and others. They showed that eradication of malaria is crucially dependent on finding and treating the large number of people in endemic areas with asymptomatic malaria, who act as a reservoir for infection.[119] The malaria parasites do not affect animal species and therefore eradication of the disease from the human population would be expected to be effective.
See also
The Global Fund to Fight AIDS, Tuberculosis and Malaria
References
1.^ Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005). "The global distribution of clinical episodes of Plasmodium falciparum malaria". Nature 434 (7030): 214–7. doi:10.1038/nature03342. PMID 15759000.
2.^ Joy D, Feng X, Mu J, et al (2003). "Early origin and recent expansion of Plasmodium falciparum.". Science 300 (5617): 318–21. doi:10.1126/science.1081449. PMID 12690197.
3.^ Escalante A, Freeland D, Collins W, Lal A (1998). "The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome.". Proc Natl Acad Sci U S A 95 (14): 8124–9. doi:10.1073/pnas.95.14.8124. PMID 9653151.
4.^ Cox F (2002). "History of human parasitology.". Clin Microbiol Rev 15 (4): 595–612. doi:10.1128/CMR.15.4.595-612.2002. PMID 12364371.
5.^ "Biography of Alphonse Laveran". The Nobel Foundation. Retrieved on 2007-06-15. ] Nobel foundation. Accessed 25 Oct 2006
6.^ "Ettore Marchiafava". Retrieved on 2007-06-15.
7.^ {Tan SY, Sung H (May 2008). "Carlos Juan Finlay (1833-1915): of mosquitoes and yellow fever". Singapore Med J 49 (5): 370–1. PMID 18465043.
8.^ Chernin E (November 1983). "Josiah Clark Nott, insects, and yellow fever". Bull N Y Acad Med 59 (9): 790–802. PMID 6140039. PMC:1911699.
9.^ Chernin E (September 1977). "Patrick Manson (1844-1922) and the transmission of filariasis". Am. J. Trop. Med. Hyg. 26 (5 Pt 2 Suppl): 1065–70. PMID 20786.
10.^ "Biography of Ronald Ross". The Nobel Foundation. Retrieved on 2007-06-15.
11.^ "Ross and the Discovery that Mosquitoes Transmit Malaria Parasites". CDC Malaria website. Retrieved on 2007-06-15.
12.^ Kaufman T, Rúveda E (2005). "The quest for quinine: those who won the battles and those who won the war.". Angew Chem Int Ed Engl 44 (6): 854–85. doi:10.1002/anie.200400663. PMID 15669029.
13.^ Kyle R, Shampe M (1974). "Discoverers of quinine". JAMA 229 (4): e320. doi:10.1001/jama.229.4.462. PMID 4600403.
14.^ Raju T (2006). "Hot brains: manipulating body heat to save the brain.". Pediatrics 117 (2): e320–1. doi:10.1542/peds.2005-1934. PMID 16452338.
15.^ Krotoski W, Collins W, Bray R, et al (1982). "Demonstration of hypnozoites in sporozoite-transmitted Plasmodium vivax infection.". Am J Trop Med Hyg 31 (6): 1291–3. PMID 6816080.
16.^ Meis J, Verhave J, Jap P, Sinden R, Meuwissen J (1983). "Malaria parasites--discovery of the early liver form.". Nature 302 (5907): 424–6. doi:10.1038/302424a0. PMID 6339945.
17.^ "Malaria". US Centers for Disease Control and Prevention (2003). Retrieved on 2008-07-20.
18.^ a b c Breman J (2001). "The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden.". Am J Trop Med Hyg 64 (1-2 Suppl): 1–11. PMID 11425172.
19.^ USAID's Malaria Programs
20.^ a b Greenwood BM, Bojang K, Whitty CJ, Targett GA (2005). "Malaria". Lancet 365: 1487–1498. doi:10.1016/S0140-6736(05)66420-3. PMID 15850634.
21.^ Hay S, Guerra C, Tatem A, Noor A, Snow R (2004). "The global distribution and population at risk of malaria: past, present, and future.". Lancet Infect Dis 4 (6): 327–36. doi:10.1016/S1473-3099(04)01043-6. PMID 15172341.
22.^ Korenromp E, Williams B, de Vlas S, Gouws E, Gilks C, Ghys P, Nahlen B (2005). "Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa.". Emerg Infect Dis 11 (9): 1410–9. PMID 16229771.
23.^ Abu-Raddad L, Patnaik P, Kublin J (2006). "Dual infection with HIV and malaria fuels the spread of both diseases in sub-Saharan Africa". Science 314 (5805): 1603–6. doi:10.1126/science.1132338. PMID 17158329.
24.^ Layne SP. "Principles of Infectious Disease Epidemiology /" (PDF). EPI 220. UCLA Department of Epidemiology. Retrieved on 2007-06-15.
25.^ Greenwood B, Mutabingwa T (2002). "Malaria in 2002". Nature 415: 670–2. doi:10.1038/415670a. PMID 11832954.
26.^ Grover-Kopec E, Kawano M, Klaver R, Blumenthal B, Ceccato P, Connor S (2005). "An online operational rainfall-monitoring resource for epidemic malaria early warning systems in Africa.". Malar J 4: 6. doi:10.1186/1475-2875-4-6. PMID 15663795.
27.^ Van Benthem B, Vanwambeke S, Khantikul N, Burghoorn-Maas C, Panart K, Oskam L, Lambin E, Somboon P (2005). "Spatial patterns of and risk factors for seropositivity for dengue infection". Am J Trop Med Hyg 72 (2): 201–8. PMID 15741558.
28.^ Trung H, Van Bortel W, Sochantha T, Keokenchanh K, Quang N, Cong L, Coosemans M (2004). "Malaria transmission and major malaria vectors in different geographical areas of Southeast Asia". Trop Med Int Health 9 (2): e473. doi:10.1046/j.1365-3156.2003.01179.x. PMID 15040560.
29.^ Keiser J, Utzinger J, Caldas de Castro M, Smith T, Tanner M, Singer B (2004). "Urbanization in sub-saharan Africa and implication for malaria control". Am J Trop Med Hyg 71 (2 Suppl): 118–27. PMID 15331827.
30.^ Hay SI, Snow RW (2006). "The Malaria Atlas Project: Developing Global Maps of Malaria Risk.". PLoS Medicine 3 (12): e473. doi:10.1371/journal.pmed.0030473.
31.^ Sachs J, Malaney P (2002). "The economic and social burden of malaria". Nature 415: 680–5. doi:10.1038/415680a. PMID 11832956.
32.^ Roll Back Malaria. "Economic costs of malaria". WHO. Retrieved on 2006-09-21.
33.^ Malaria life cycle & pathogenesis. Malaria in Armenia. Accessed October 31, 2006.
34.^ Idro, R; Otieno G, White S, Kahindi A, Fegan G, Ogutu B, Mithwani S, Maitland K, Neville BG, Newton CR. "Decorticate, decerebrate and opisthotonic posturing and seizures in Kenyan children with cerebral malaria". Malaria Journal 4 (57): 57. doi:10.1186/1475-2875-4-57. PMID 16336645. Retrieved on 2007-01-21.
35.^ Boivin, M.J., "Effects of early cerebral malaria on cognitive ability in Senegalese children," Journal of Developmental and Behavioral Pediatrics 23, no. 5 (October 2002): 353–64. Holding, P.A. and Snow, R.W., "Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence," American Journal of Tropical Medicine and Hygiene 64, suppl. nos. 1–2 (January–February 2001): 68–75.
36.^ a b c Trampuz A, Jereb M, Muzlovic I, Prabhu R (2003). "Clinical review: Severe malaria.". Crit Care 7 (4): 315–23. doi:10.1186/cc2183. PMID 12930555.
37.^ Kain K, Harrington M, Tennyson S, Keystone J (1998). "Imported malaria: prospective analysis of problems in diagnosis and management.". Clin Infect Dis 27 (1): 142–9. doi:10.1086/514616. PMID 9675468.
38.^ Mockenhaupt F, Ehrhardt S, Burkhardt J, Bosomtwe S, Laryea S, Anemana S, Otchwemah R, Cramer J, Dietz E, Gellert S, Bienzle U (2004). "Manifestation and outcome of severe malaria in children in northern Ghana.". Am J Trop Med Hyg 71 (2): 167–72. PMID 15306705.
39.^ Carter JA, Ross AJ, Neville BG, Obiero E, Katana K, Mung'ala-Odera V, Lees JA, Newton CR (2005). "Developmental impairments following severe falciparum malaria in children". Trop Med Int Health 10: 3–10. doi:10.1111/j.1365-3156.2004.01345.x. PMID 15655008.
40.^ Adak T, Sharma V, Orlov V (1998). "Studies on the Plasmodium vivax relapse pattern in Delhi, India.". Am J Trop Med Hyg 59 (1): 175–9. PMID 9684649.
41.^ Mendis K, Sina B, Marchesini P, Carter R (2001). "The neglected burden of Plasmodium vivax malaria." (PDF). Am J Trop Med Hyg 64 (1-2 Suppl): 97–106. PMID 11425182.
42.^ Escalante A, Ayala F (1994). "Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences.". Proc Natl Acad Sci U S A 91 (24): 11373–7. doi:10.1073/pnas.91.24.11373. PMID 7972067.
43.^ Garnham, PCC (1966). Malaria parasites and other haemosporidia. Blackwell Scientific Publications.
44.^ Investing in Animal Health Research to Alleviate Poverty. International Livestock Research Institute. Permin A. and Madsen M. (2001) Appendix 2: review on disease occurrence and impact (smallholder poultry). Accessed 29 Oct 2006
45.^ Atkinson CT, Woods KL, Dusek RJ, Sileo LS, Iko WM (1995). "Wildlife disease and conservation in Hawaii: pathogenicity of avian malaria (Plasmodium relictum) in experimentally infected iiwi (Vestiaria coccinea)". Parasitology 111 Suppl: S59–69. PMID 8632925.
46.^ Talman A, Domarle O, McKenzie F, Ariey F, Robert V (2004). "Gametocytogenesis: the puberty of Plasmodium falciparum.". Malar J 3: 24. doi:10.1186/1475-2875-3-24. PMID 15253774.
47.^ Marcucci C, Madjdpour C, Spahn D (2004). "Allogeneic blood transfusions: benefit, risks and clinical indications in countries with a low or high human development index.". Br Med Bull 70: 15–28. doi:10.1093/bmb/ldh023. PMID 15339855.
48.^ Bledsoe, G. H. (December 2005) "Malaria primer for clinicians in the United States" Southern Medical Journal 98(12): pp. 1197-204, (PMID: 16440920);
49.^ Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, Krueger A, Pollok JM, Menard R, Heussler VT (2006). "Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids". Science 313: 1287–1490. doi:10.1126/science.1129720. PMID 16888102.
50.^ Cogswell F (1992). "The hypnozoite and relapse in primate malaria.". Clin Microbiol Rev 5 (1): 26–35. PMID 1735093.
51.^ a b Chen Q, Schlichtherle M, Wahlgren M (2000). "Molecular aspects of severe malaria.". Clin Microbiol Rev 13 (3): 439–50. doi:10.1128/CMR.13.3.439-450.2000. PMID 10885986.
52.^ Adams S, Brown H, Turner G (2002). "Breaking down the blood-brain barrier: signaling a path to cerebral malaria?". Trends Parasitol 18 (8): 360–6. doi:10.1016/S1471-4922(02)02353-X. PMID 12377286.
53.^ Lindsay S, Ansell J, Selman C, Cox V, Hamilton K, Walraven G (2000). "Effect of pregnancy on exposure to malaria mosquitoes.". Lancet 355 (9219): 1972. doi:10.1016/S0140-6736(00)02334-5. PMID 10859048.
54.^ van Geertruyden J, Thomas F, Erhart A, D'Alessandro U (2004). "The contribution of malaria in pregnancy to perinatal mortality.". Am J Trop Med Hyg 71 (2 Suppl): 35–40. PMID 15331817.
55.^ Rodriguez-Morales AJ, Sanchez E, Vargas M, Piccolo C, Colina R, Arria M, Franco-Paredes C (2006). "Pregnancy outcomes associated with Plasmodium vivax malaria in northeastern Venezuela". Am J Trop Med Hyg 74: 755–757. PMID 16687675.
56.^ Kwiatkowski, DP (2005). "How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria". Am J Hum Genet 77: 171–92. doi:10.1086/432519. PMID 16001361.
57.^ Carter R, Mendis KN (2002). "Evolutionary and historical aspects of the burden of malaria". Clin. Microbiol. Rev. 15 (4): 564–94. doi:10.1128/CMR.15.4.564-594.2002. PMID 12364370.
58.^ Verra F, Luoni G, Calissano C, Troye-Blomberg M, Perlmann P, Perlmann H, Arcà B, Sirima B, Konaté A, Coluzzi M, Kwiatkowski D, Modiano D (2004). "IL4-589C/T polymorphism and IgE levels in severe malaria". Acta Trop. 90 (2): 205–9. doi:10.1016/j.actatropica.2003.11.014. PMID 15177147.
59.^ Beare NA et al. Am J Trop Med Hyg. 2006 Nov;75(5):790-797.
60.^ Redd S, Kazembe P, Luby S, Nwanyanwu O, Hightower A, Ziba C, Wirima J, Chitsulo L, Franco C, Olivar M (2006). "Clinical algorithm for treatment of Plasmodium falciparum malaria in children". Lancet 347 (8996): 80. doi:10.1016/S0140-6736(96)90404-3. PMID 8551881. .
61.^ Warhurst DC, Williams JE (1996). "Laboratory diagnosis of malaria". J Clin Pathol 49: 533–38. doi:10.1136/jcp.49.7.533. PMID 8813948.
62.^ Pattanasin S, Proux S, Chompasuk D, Luwiradaj K, Jacquier P, Looareesuwan S, Nosten F (2003). "Evaluation of a new Plasmodium lactate dehydrogenase assay (OptiMAL-IT®) for the detection of malaria". Transact Royal Soc Trop Med 97: 672–4. doi:10.1016/S0035-9203(03)80100-1. PMID 16117960.
63.^ Ling IT., Cooksley S., Bates PA., Hempelmann E., Wilson RJM. (1986). "Antibodies to the glutamate dehydrogenase of Plasmodium falciparum.". Parasitology 92,: 313–24. PMID 3086819.
64.^ Redd S, Kazembe P, Luby S, Nwanyanwu O, Hightower A, Ziba C, Wirima J, Chitsulo L, Franco C, Olivar M (2006). "Clinical algorithm for treatment of Plasmodium falciparum malaria in children". Lancet 347 (8996): 80. doi:10.1016/S0140-6736(96)90404-3. PMID 8551881. .
65.^ Mens PF, Schoone GJ, Kager PA, Schallig HDFH. (2006). "Detection and identification of human Plasmodium species with real-time quantitative nucleic acid sequence-based amplification". Malaria Journal 5 (80): 80. doi:10.1186/1475-2875-5-80.
66.^ Redd S, Kazembe P, Luby S, Nwanyanwu O, Hightower A, Ziba C, Wirima J, Chitsulo L, Franco C, Olivar M (2006). "Clinical algorithm for treatment of Plasmodium falciparum malaria in children". Lancet 347 (8996): 80. doi:10.1016/S0140-6736(96)90404-3. PMID 8551881. .
67.^ If I get malaria, will I have it for the rest of my life? CDC publication, Accessed 14 Nov 2006
68.^ Tinto H, Rwagacondo C, Karema C, et al. (2006). "In-vitro susceptibility of Plasmodium falciparum to monodesethylamodiaquine, dihydroartemsinin and quinine in an area of high chloroquine resistance in Rwanda". Trans R Soc Trop Med Hyg 100 (6): 509–14. doi:10.1016/j.trstmh.2005.09.018.
69.^ Murphy S, Harrison T, Hamm H, Lomasney J, Mohandas N, Haldar K (Dec 2006). "Erythrocyte G protein as a novel target for malarial chemotherapy". PLoS Med 3 (12): e528. doi:10.1371/journal.pmed.0030528. PMID 17194200.
70.^ Prescription drugs for malaria Retrieved February 27, 2007.
71.^ Trager W, Jensen JB. (1976). "Human malaria parasites in continuous culture". Science 193(4254): 673–5. doi:10.1126/science.781840. PMID 781840.
72.^ Senior K (2005). "Shortfall in front-line antimalarial drug likely in 2005". Lancet Infect Dis 5 (2): 75. PMID 15702504.
73.^ Rwagacondo C, Karema C, Mugisha V, Erhart A, Dujardin J, Van Overmeir C, Ringwald P, D'Alessandro U (2004). "Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria". Trop Med Int Health 9 (10): 1091–8. doi:10.1111/j.1365-3156.2004.01316.x. PMID 15482401. .
74.^ Eckstein-Ludwig U, Webb R, Van Goethem I, East J, Lee A, Kimura M, O'Neill P, Bray P, Ward S, Krishna S (2003). "Artemisinins target the SERCA of Plasmodium falciparum.". Nature 424 (6951): 957–61. doi:10.1038/nature01813. PMID 12931192.
75.^ Uhlemann A, Cameron A, Eckstein-Ludwig U, Fischbarg J, Iserovich P, Zuniga F, East M, Lee A, Brady L, Haynes R, Krishna S (2005). "A single amino acid residue may determine the sensitivity of SER`CAs to artemisinins.". Nat Struct Mol Biol 12 (7): 628–9. doi:10.1038/nsmb947. PMID 15937493.
76.^ Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier J, Zhou B (2005). "Yeast model uncovers dual roles of mitochondria in action of artemisinin.". PLoS Genet 1 (3): e36. doi:10.1371/journal.pgen.0010036. PMID 16170412.
77.^ Malaria drug offers new hope. BBC News 2002-02-15.
78.^ One step closer to conquering malaria
79.^ Salom-Roig, X. et al. (2005) Dual molecules as new antimalarials. Combinatorial Chemistry & High Throughput Screening 8:49-62.
80.^ "Herbicides as a treatment for malaria". Retrieved on 2007-09-25.
81.^ Khöler, Sabine (March 1997). "A Plastid of Probable Green Algal Origin in Apicomplexan Parasites". Science 275 (5305): 1485–1489. doi:10.1126/science.275.5305.1485. PMID 9045615.
82.^ Gardner, Malcom (November 1998). "Chromosome 2 Sequence of the Human Malaria Parasite Plasmodium falciparum". Science 282 (5391): 1126–1132. doi:10.1126/science.282.5391.1126. PMID 9804551.
83.^ Foth, Bernado (January 2003). "Dissecting Apicoplast Targeting in the Malaria Parasite Plasmodium falciparum". Science 299 (5607): 705–708. doi:10.1126/science.1078599. PMID 12560551.
84.^ Medecins Sans Frontieres, "What is the Cost and Who Will Pay?"
85.^ Lon CT, Tsuyuoka R, Phanouvong S, et al. (2006). "Counterfeit and substandard antimalarial drugs in Cambodia". Trans R Soc Trop Med Hyg 100 (11): 1019–24. doi:10.1016/j.trstmh.2006.01.003.
86.^ U. S. Pharmacopeia (2004). "Fake antimalarials found in Yunan province, China" (PDF). Retrieved on 2006-10-06.
87.^ Newton PN Green MD, Fernández FM, Day NPJ, White NJ. (2006). "Counterfeit anti-infective drugs". Lancet Infect Dis 6 (9): 602–13. doi:10.1016/S1473-3099(06)70581-3. PMID 16931411.
88.^ Jane Parry (2005). "WHO combats counterfeit malaria drugs in Asia". Retrieved on 2008-07-19.
89.^ a b c Hull, Kevin. (2006) "Malaria: Fever Wars". PBS Documentary
90.^ Barat L (2006). "Four malaria success stories: how malaria burden was successfully reduced in Brazil, Eritrea, India, and Vietnam.". Am J Trop Med Hyg 74 (1): 12–6. PMID 16407339.
91.^ Killeen G, Fillinger U, Kiche I, Gouagna L, Knols B (2002). "Eradication of Anopheles gambiae from Brazil: lessons for malaria control in Africa?". Lancet Infect Dis 2 (10): e192. doi:10.1016/S1473-3099(02)00397-3. PMID 12383612.
92.^ Gladwell, Malcolm. (2001-07-02). "The Mosquito Killer", The New Yorker.
93.^ Imperial College, London, "Scientists create first transgenic malaria mosquito", 2000-06-22.
94.^ Ito J, Ghosh A, Moreira LA, Wimmer EA, Jacobs-Lorena M (2002). "Transgenic anopheline mosquitoes impaired in transmission of a malaria parasite". Nature 417: 387–8. doi:10.1038/417452a. PMID 12024215.
95.^ BBC NEWS, Sea cucumber 'new malaria weapon'
96.^ Yoshida S, Shimada Y, Kondoh D, et al (2007). "Hemolytic C-type lectin CEL-III from sea cucumber expressed in transgenic mosquitoes impairs malaria parasite development". PLoS Pathog. 3 (12): e192. doi:10.1371/journal.ppat.0030192. PMID 18159942.
97.^ Tia E, Akogbeto M, Koffi A, et al (2006). "[Pyrethroid and DDT resistance of Anopheles gambiae s.s. (Diptera: Culicidae) in five agricultural ecosystems from Côte-d'Ivoire]" (in French). Bulletin de la Société de pathologie exotique (1990) 99 (4): 278–82. PMID 17111979.
98.^ Indoor Residual Spraying: Use of Indoor Residual Spraying for Scaling Up Global Malaria Control and Elimination. World Health Organization, 2006.
99.^ 10 Things You Need to Know about DDT Use under The Stockholm Convention
100.^ The Stockholm Convention on persistent organic pollutants
101.^ Bachou H, Tylleskar T, Kaddu-Mulindwa DH, Tumwine JK. (2006). "Bacteraemia among severely malnourished children infected and uninfected with the human immunodeficiency virus-1 in Kampala, Uganda". BMC Infect Dis 6: 160. doi:10.1186/1471-2334-6-160.
102.^ New Mosquito Nets Could Help Fight Malaria in Africa
103.^ The Economist. "Traditional Economy of the Kavango", Economist Documentary.
104.^ Rowland M, Durrani N, Hewitt S, Mohammed N, Bouma M, Carneiro I, Rozendaal J, Schapira A (1999). "Permethrin-treated chaddars and top-sheets: appropriate technology for protection against malaria in Afghanistan and other complex emergencies.". Trans R Soc Trop Med Hyg 93 (5): 465–72. doi:10.1016/S0035-9203(99)90341-3. PMID 10696399.
105.^ "Fungus 'may help malaria fight'", BBC News, 2005-06-09
106.^ a b Nussenzweig R, Vanderberg J, Most H, Orton C (1967). "Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei". Nature 216 (5111): 160–2. doi:10.1038/216160a0. PMID 6057225.
107.^ Hoffman SL, Goh LM, Luke TC, et al (2002). "Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites". J. Infect. Dis. 185 (8): 1155–64. doi:10.1086/339409. PMID 11930326.
108.^ Sanaria Press and Publications
109.^ Health | You can get paid to catch malaria | Seattle Times Newspaper
110.^ Zavala F, Cochrane A, Nardin E, Nussenzweig R, Nussenzweig V (1983). "Circumsporozoite proteins of malaria parasites contain a single immunodominant region with two or more identical epitopes". J Exp Med 157 (6): 1947–57. doi:10.1084/jem.157.6.1947.
111.^ Hollingdale M, Nardin E, Tharavanij S, Schwartz A, Nussenzweig R (1984). "Inhibition of entry of Plasmodium falciparum and P. vivax sporozoites into cultured cells; an in vitro assay of protective antibodies". J Immunol 132 (2): 909–13. PMID 6317752.
112.^ a b Matuschewski K (2006). "Vaccine development against malaria". Curr Opin Immunol 18 (4): 449–57. doi:10.1016/j.coi.2006.05.004. PMID 16765576.
113.^ Gardner M, Hall N, Fung E, et al (2002). "Genome sequence of the human malaria parasite Plasmodium falciparum.". Nature 370 (6906): 1543. doi:10.1038/nature01097. PMID 12368864.
114.^ Heppner DG, Kester KE, Ockenhouse CF, et al (2005). "Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research". Vaccine 23 (17-18): 2243–50. doi:10.1016/j.vaccine.2005.01.142. PMID 15755604.
115.^ Alonso PL, Sacarlal J, Aponte JJ, et al (2004). "Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial". Lancet 364 (9443): 1411–20. doi:10.1016/S0140-6736(04)17223-1. PMID 15488216.
116.^ Aponte JJ, Aide P, Renom M et al (2007). "Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial". Lancet 370: 1543. doi:10.1016/S0140-6736(07)61542-6.
117.^ Africa: Malaria - Vaccine Expected in 2011. Accra Mail. 9 January 2007. Accessed 15 January 2007.
118.^ "What is Malariacontrol.net". AFRICA@home. Retrieved on 2007-03-11.
119.^ Águas R, White LJ, Snow RW, Gomes MGM (2008). "Prospects for malaria eradication in sub-Saharan Africa". PLoS ONE 3 (3): 1543. doi:10.1371/journal.pone.0001767.
http://en.wikipedia.org/wiki/Dengue_fever
Dengue fever
From Wikipedia, the free encyclopedia
Jump to: navigation, search
"Dengue Fever" redirects here. For the band of the same name, see Dengue Fever (band).
Dengue virus
A TEM micrograph showing dengue virus
Virus classification
Group:
Group IV ((+)ssRNA)
Family:
Flaviviridae
Genus:
Flavivirus
Species:
Dengue virus
Dengue fever
Classification and external resources
ICD-10
A90.
ICD-9
061
DiseasesDB
3564
MedlinePlus
001374
eMedicine
med/528
MeSH
C02.782.417.214
Dengue fever (IPA: /'d??ge?/) and dengue hemorrhagic fever (DHF) are acute febrile diseases, found in the tropics and Africa, and caused by four closely related virus serotypes of the genus Flavivirus, family Flaviviridae.[1] The geographical spread is similar to malaria, but unlike malaria, dengue is often found in urban areas of tropical nations, including Puerto Rico, Singapore, Malaysia, Taiwan, Indonesia, Philippines, India and Brazil. Each serotype is sufficiently different that there is no cross-protection and epidemics caused by multiple serotypes (hyperendemicity) can occur. Dengue is transmitted to humans by the Aedes aegypti (rarely Aedes albopictus) mosquito, which feeds during the day.[2]
Contents
[hide]
1 Signs and symptoms
2 Diagnosis
3 Treatment
3.1 Emerging treatments
4 Epidemiology
5 Prevention
5.1 Vaccine development
5.2 Mosquito control
5.3 Personal protection
5.4 Potential antiviral approaches
6 Recent outbreaks
6.1 Americas
6.2 Asia Pacific
7 History
8 Footnotes
9 References
10 External links
[edit] Signs and symptoms
This infectious disease is manifested by a sudden onset of fever, with severe headache, muscle and joint pains (myalgias and arthralgias—severe pain gives it the name break-bone fever or bonecrusher disease) and rashes. The dengue rash is characteristically bright red petechiae and usually appears first on the lower limbs and the chest; in some patients, it spreads to cover most of the body. There may also be gastritis with some combination of associated abdominal pain, nausea, vomiting or diarrhea.
Other symptoms include
fever;
chills;
constant headaches;
bleeding from nose, mouth or gums;
severe dizziness; and,
loss of appetite.
Some cases develop much milder symptoms which can, when no rash is present, be misdiagnosed as influenza or other viral infection. Thus travelers from tropical areas may inadvertently pass on dengue in their home countries, having not been properly diagnosed at the height of their illness. Patients with dengue can pass on the infection only through mosquitoes or blood products and only while they are still febrile.
The classic dengue fever lasts about six to seven days, with a smaller peak of fever at the trailing end of the disease (the so-called "biphasic pattern"). Clinically, the platelet count will drop until the patient's temperature is normal.
Cases of DHF also show higher fever, haemorrhagic phenomena, thrombocytopenia, and haemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate.
[edit] Diagnosis
The diagnosis of dengue is usually made clinically. The classic picture is high fever with no localising source of infection, a petechial rash with thrombocytopenia and relative leukopenia.
The WHO definition of dengue haemorrhagic fever has been in use since 1975; all four criteria must be fulfilled:[3]
1.Fever, bladder problem, constant headaches, severe dizziness and loss of appetite.
2.Hemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
3.Thrombocytopenia (<100,000 platelets per mm³ or estimated as less than 3 platelets per high power field)
4.Evidence of plasma leakage (hematocrit more than 20% higher than expected, or drop in haematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)
Dengue shock syndrome is defined as dengue hemorrhagic fever plus:
Weak rapid pulse,
Narrow pulse pressure (less than 20 mm Hg) or,
Cold, clammy skin and restlessness.
Serology and polymerase chain reaction (PCR) studies are available to confirm the diagnosis of dengue if clinically indicated.
[edit] Treatment
The mainstay of treatment is supportive therapy. Increased oral fluid intake is recommended to prevent dehydration. Supplementation with intravenous fluids may be necessary to prevent dehydration and significant concentration of the blood if the patient is unable to maintain oral intake. A platelet transfusion is indicated in rare cases if the platelet level drops significantly (below 20,000) or if there is significant bleeding.
The presence of melena may indicate internal gastrointestinal bleeding requiring platelet and/or red blood cell transfusion.
Aspirin and non-steroidal anti-inflammatory drugs should be avoided as these drugs may worsen the bleeding tendency associated with some of these infections. Patients may receive paracetamol preparations to deal with these symptoms if dengue is suspected.[4]
[edit] Emerging treatments
Emerging evidence suggests that mycophenolic acid and ribavirin inhibit dengue replication. Initial experiments showed a fivefold increase in defective viral RNA production by cells treated with each drug.[5] In vivo studies, however, have not yet been done.
[edit] Epidemiology
World-wide dengue distribution, 2006. Red: Epidemic dengue. Blue: Aedes aegypti.
World-wide dengue distribution, 2000
The first epidemics occurred almost simultaneously in Asia, Africa, and North America in the 1780s. The disease was identified and named in 1779. A global pandemic began in Southeast Asia in the 1950s and by 1975 DHF had become a leading cause of death among children in many countries in that region. Epidemic dengue has become more common since the 1980s. By the late 1990s, dengue was the most important mosquito-borne disease affecting humans after malaria, there being around 40 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever each year. There was a serious outbreak in Rio de Janeiro in February 2002 affecting around one million people and killing sixteen.
On March 20, 2008, the secretary of health of the state of Rio de Janeiro, Sérgio Côrtes, announced that 23,555 cases of dengue, including 30 deaths, had been recorded in the state in less than three months. Côrtes said, "I am treating this as an epidemic because the number of cases is extremely high." Federal Minister of Health José Gomes Temporão also announced that he was forming a panel to respond to the situation. Cesar Maia, mayor of the city of Rio de Janeiro, denied that there was serious cause for concern, saying that the incidence of cases was in fact declining from a peak at the beginning of February. [6] By April 3, 2008, the number of cases reported rose to 55,000 [7]
Significant outbreaks of dengue fever tend to occur every five or six months. The cyclicity in numbers of dengue cases is thought to be the result of seasonal cycles interacting with a short-lived cross-immunity for all four strains, in people who have had dengue (Wearing and Rohani 2006). When the cross-immunity wears off, the population is then more susceptible to transmission whenever the next seasonal peak occurs. Thus in the longer term of several years, there tend to remain large numbers of susceptible people in the population despite previous outbreaks because there are four different strains of the dengue virus and because of new susceptible individuals entering the target population, either through childbirth or immigration.
There is significant evidence, originally suggested by S.B. Halstead in the 1970s, that dengue hemorrhagic fever is more likely to occur in patients who have secondary infections by serotypes different from the primary infection. One model to explain this process is known as antibody-dependent enhancement (ADE), which allows for increased uptake and virion replication during a secondary infection with a different strain. Through an immunological phenomenon, known as original antigenic sin, the immune system is not able to adequately respond to the stronger infection, and the secondary infection becomes far more serious.[8] This process is also known as superinfection (Nowak and May 1994; Levin and Pimentel 1981).
In Singapore, there are about 4,000–5,000 reported cases of dengue fever or dengue haemorrhagic fever every year. In the year 2003, there were six deaths from dengue shock syndrome.[citation needed] It is believed that the reported cases of dengue are an underrepresentation of all the cases of dengue as it would ignore subclinical cases and cases where the patient did not present for medical treatment. With proper medical treatment, the mortality rate for dengue can therefore be brought down to less than 1 in 1000.[citation needed]
[edit] Prevention
[edit] Vaccine development
There is no commercially available vaccine for the dengue flavivirus. However, one of the many ongoing vaccine development programs is the Pediatric Dengue Vaccine Initiative which was set up in 2003 with the aim of accelerating the development and introduction of dengue vaccine(s) that are affordable and accessible to poor children in endemic countries.[9] Thai researchers are testing a dengue fever vaccine on 3,000–5,000 human volunteers after having successfully conducted tests on animals and a small group of human volunteers.[10] A number of other vaccine candidates are entering phase I or II testing.[11]
[edit] Mosquito control
A field technician looking for larvae in standing water containers during the 1965 Aedes aegypti eradication program in Miami, Florida. In the 1960s, a major effort was made to eradicate the principal urban vector mosquito of dengue and yellow fever viruses, Aedes aegypti, from southeast United States. Courtesy: Centers for Disease Control and Prevention Public Health Image Library
Primary prevention of dengue mainly resides in mosquito control. There are two primary methods: larval control and adult mosquito control. In urban areas, Aedes mosquitos breed on water collections in artificial containers such as plastic cups, used tires, broken bottles, flower pots, etc. Continued and sustained artificial container reduction or periodic draining of artificial containers is the most effective way of reducing the larva and thereby the aedes mosquito load in the community. Larvicide treatment is another effective way of control the vector larvae but the larvicide chosen should be long lasting and preferably have World Health Organization clearance for use in drinking water. There are some very effective insect growth regulators (IGR`s) available which are both safe and long alasting e.g. pyriproxyfen. For reducing the adult mosquito load, fogging with insecticide is somewhat effective.
Prevention of mosquito bites is another way of preventing disease. This can be achieved either by personal protection or by using mosquito nets. In 1998, scientists from the Queensland Institute of Research in Australia and Vietnam's Ministry of Health introduced a scheme that encouraged children to place a water bug, the crustacean Mesocyclops, in water tanks and discarded containers where the Aedes aegypti mosquito was known to thrive. This method is viewed as being more cost-effective and more environmentally friendly than pesticides, though not as effective, and requires the ongoing participation of the community.[12]
[edit] Personal protection
Personal prevention consists of the use of mosquito nets, repellents containing NNDB or DEET, covering exposed skin, use of DEET-impregnated bednets, and avoiding endemic areas.
[edit] Potential antiviral approaches
In cell culture experiments[13] and mice [14] Morpholino antisense oligos have shown specific activity against Dengue virus.
The yellow fever vaccine (YF-17D) is a vaccine for a related Flavivirus,[clarify] thus the chimeric replacement of yellow fever vaccine with dengue has been often suggested[clarify] but no full scale studies have been conducted to date.[15]
In 2006, a group of Argentine scientists discovered the molecular replication mechanism of the virus, which could be attacked by disruption of the polymerase's work.[16]
[edit] Recent outbreaks
A public service ad teaching people how to prevent dengue and yellow fever in Encarnación, Paraguay (2007)
2005 dengue outbreak (edit)
Country
Cases
Deaths
Date of Information
Sources
Cambodia
20,000
38
Sep.
[1]
Costa Rica
19,000
1
7 Sep.
[2]
India, (West Bengal)
90,000
1,500
Sep.
[3]
Indonesia
80,837
1,099
Jan. 2006
[4]
Malaysia
32,950
83
1 Nov.
[5]
Martinique
6,000
2
26 Sep.
[6]
Philippines
21,537
280
2 Oct.
[7]
Singapore
12,700
19
22 Oct.
[8]
Sri Lanka
3,000
-
16 Sep.
[9]
Thailand
31,000
58
Sep.
[10]
Vietnam
20,000
28
4 Oct.
[11]
Pakistan
4,800
50
11 Dec 2006.
[12]
Total†
232,724
16,673
—
—
†For listed countries only. World Health Organization estimates that there may be 50 million cases of dengue infection worldwide each year. [13]
During the first months of 2007, over 16,000 cases have been reported in Paraguay and in the end of the year, more than 100.000, of which around 300 or 400 have been detected as DHF cases. Ten deaths have also been reported, including a high ranking member of the Ministry of Health. One Department of Health official resigned because he had approved the use of expired batches of insecticide to control the mosquito vectors of dengue.[17][18] The disease has propagated to Argentina (where it is not considered endemic) by people who recently arrived from Paraguay.[19] In the Brazilian state of Mato Grosso do Sul, which borders on Paraguay, the number of cases in March 2007 is estimated to be more than 45,000.[18] Epidemics in the states of Ceará, Pará, São Paulo, and Rio de Janeiro have taken the Brazilian national tally of cases to over 70,000, with upwards of 80 deaths.[20] Larvae have also been found in Parana state. The proportion of cases registered as DHF is reported to be higher than in previous years.[citation needed]
[edit] Americas
Puerto Rico: [21](August 2007) 2,343 confirmed cases of dengue in 2007.
Dominican Republic:[not in citation given][22](August – October 2006) 4,968 cases with 44 dead
Cuba: Media reports [23][24][25][26] (dated September and October 2006) speculate on an outbreak although there is no official report
Brazil: 2008 Health officials say an outbreak of dengue fever has infected more than 110,000 people in Rio de Janeiro state and claimed at least 95 lives since January 1. An outbreak of Dengue in the first seven months of 2007 reported more than 438,000 cases of dengue fever, with 97 deaths.[27]
Mexico: As of October 2007 there is a serious problem in Monterrey, Nuevo Leon almost reaching epidemic proportions.[citation needed]
[edit] Asia Pacific
See also: 2006 dengue outbreak in Pakistan, 2005 dengue outbreak in Singapore, and 2006 dengue outbreak in India
Australia: 2006 March 15, 2 confirmed cases at Gordonvale, Cairns, Queensland.
China: September 2006, 70 cases since June in Guangzhou,Guangdong.[28]
Cook Islands: [29](October 2006 – January 2007) 460 cases.
India: 2006 September, more than 400 cases and 22 deaths were reported due to dengue fever in New Delhi.[30] By October 7, 2006, reports were of 3,331 cases of the mosquito-borne virus and a death toll of 49.[31]
Indonesia: 2004 80,000 infected with 800 deaths.
Malaysia: January 2005 33,203 cases.
Pakistan: 2006 Over 3,230 cases, 50 deaths.
Karachi 2006 October, the number of infected patients rose to 1,836 of which 30 had died.
Lahore, 2006 October 23, the disease shifted to Lahore during the holidays with the luggage of some people travelling to their homes to celebrate Eid. The number of infected patients is 400 by October 31, of which 4 had died.
Philippines: [32](January – August 2006) 13,468 cases with 167 dead.
Singapore: 2007 - more than 4029 cases, 8 deaths; 29 September 2005 at least 13 deaths; 2004 - 9,460 cases; 2003 - 4,788 cases.
Thailand: May 2005 , 7,200 infected. At least 12 dead.
[edit] History
The origins of the word dengue are not clear, but one theory is that it is derived from the Swahili phrase "Ka-dinga pepo", which describes the disease as being caused by an evil spirit.[33] The Swahili word "dinga" may possibly have its origin in the Spanish word "dengue" (fastidious or careful), describing the gait of a person suffering dengue fever[34] or, alternatively, the Spanish word may derive from the Swahili.[35] It may also be attributed to the phrase meaning "Break bone fever", referencing the fact that pain in the bones is a common symptom.
Outbreaks resembling dengue fever have been reported throughout history.[36] The first definitive case report dates from 1789 and is attributed to Benjamin Rush, who coined the term "breakbone fever" (because of the symptoms of myalgia and arthralgia). The viral etiology and the transmission by mosquitoes were deciphered only in the 20th century. Population movements during World War II spread the disease globally.
In 2007 replication mechanism of the virus was interrupted by interception of the viral protease [14], and currently a project to identify new protease interception mechanisms of the whole familly of the virus has been launched (Dengue virus belong to the familly Flaviviridae, which includes among others HCV, West Nile and Yellow fever viruses). The software and information about the project can be found at the World Community Grid web site.[15]
[edit] Footnotes
1.^ "Chapter 4, Prevention of Specific Infectious Diseases". CDC Traveler's Health: Yellow Book. Retrieved on 2007-05-20.
2.^ Dengue Fever – Information Sheet. World Health Organization, October 9, 2006. Retrieved on 2007-11-30.
3.^ Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd edition. World Health Organization. Retrieved on 2007-11-30.
4.^ Dengue and Dengue Hemorrhagic Fever: Information for Health Care Practitioners. Center for Disease Control. October 22, 2007 Retrieved on 2007-11-30.
5.^ Takhampunya R, Ubol S, Houng HS, Cameron CE, Padmanabhan R (2006). "Inhibition of dengue virus replication by mycophenolic acid and ribavirin". J. Gen. Virol. 87 (Pt 7): 1947–52. doi:10.1099/vir.0.81655-0. PMID 16760396.
6.^ Fernanda Pontes (20 March 2008), "Secretário estadual de Saúde Sérgio Côrtes admite que estado vive epidemia de dengue", O Globo Online, <http://oglobo.globo.com/rio/mat/2008/03/20/secretario_estadual_de_saude_sergio_cortes_admite_que_estado_vive_epidemia_de_dengue-426368388.asp> .
7.^ CNN (3 April 2008), "Thousands hit by Brazil outbreak of dengue", CNN, <http://www.cnn.com/2008/HEALTH/conditions/04/03/brazil.dengue/index.html> .
8.^ Rothman AL (2004). "Dengue: defining protective versus pathologic immunity". J. Clin. Invest. 113 (7): 946–51. doi:10.1172/JCI200421512. PMID 15057297.
9.^ "Pediatric Dengue Vaccine Initiative website". International Vaccine Institute. Retrieved on 2007-11-30.
10.^ "Thailand to test Mahidol-developed dengue vaccine prototype". People's Daily Online (2005-09-05). Retrieved on 2006-10-08.
11.^ Edelman R (2007). "Dengue vaccines approach the finish line". Clin. Infect. Dis. 45 Suppl 1: S56–60. doi:10.1086/518148. PMID 17582571.
12.^ "Water bug aids dengue fever fight", BBC News (February 11, 2005). Retrieved on 2007-11-30.
13.^ Kinney RM, Huang CY, Rose BC, et al (2005). "Inhibition of dengue virus serotypes 1 to 4 in vero cell cultures with morpholino oligomers". J. Virol. 79 (8): 5116–28. doi:10.1128/JVI.79.8.5116-5128.2005. PMID 15795296.
14.^ Burrer R, Neuman BW, Ting JP, et al (2007). "Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models". J. Virol. 81 (11): 5637–48. doi:10.1128/JVI.02360-06. PMID 17344287.
15.^ Querec T, Bennouna S, Alkan S, et al (2006). "Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity". J. Exp. Med. 203 (2): 413–24. doi:10.1084/jem.20051720. PMID 16461338.
16.^ Filomatori CV, Lodeiro MF, Alvarez DE, Samsa MM, Pietrasanta L, Gamarnik AV (2006). "A 5' RNA element promotes dengue virus RNA synthesis on a circular genome". Genes Dev. 20 (16): 2238–49. doi:10.1101/gad.1444206. PMID 16882970.
17.^ "Dengue sparks Paraguay emergency". BBC News (2 March 2007). Retrieved on 2007-06-19.
18.^ a b "Paraguay dengue official sacked". BBC News (6 March 2007). Retrieved on 2007-06-19.
19.^ (Spanish) "Hay 93 casos de dengue", Clarín (22 February 2007).
20.^ (Spanish) "Dengue Outbreak Sweeps Through Rio", New York Times (15 April 2008).
21.^ "Dengue fever surging in Puerto Rico", MSNBC, Telemundo (August 08, 2007). Retrieved on 2007-13-09.
22.^ (Spanish) Batista, L.; A Santiago Díaz. "Más de 4,968 afectados por dengue", Diario Libre. Retrieved on 2006-10-19.
23.^ "Protecting the Revolution", Strategypage.com (September 17, 2006). Retrieved on 2006-10-07.
24.^ Acosta, Dalia (2006-09-12). "War on Mosquitoes Continues During Global Summit", Inter Press Service. Retrieved on 2006-10-07.
25.^ "Cuba wages war on tiny enemy", Independent Online, South Africa (September 25, 2006). Retrieved on 2006-10-07.
26.^ "Cuba waging war against dengue fever", Miami Herald (October 7, 2006). Retrieved on 2006-10-07.
27.^ "State secretary of Health".
28.^ China, Dengue Fever Cases Jump. Taipei Times, 29 August, 2006.
29.^ "460 people in Cook Islands affected by Dengue Fever outbreak", Radio New Zealand International (15 January 2007). Retrieved on 2007-01-15.
30.^ "Dengue fever kills 14 in India, affects more than 400", International Herald Tribune, Associated Press News (October 2, 2006). Retrieved on 2006-10-02].
31.^ India says dengue outbreak serious as death toll rises Pratap Chakravarty, news.yahoo.com, 7 October 2006. Retrieved 8 October 2006.
32.^ Santos, Tina (September 10, 2006). "DOH names dengue-hit areas in metropolis", Philippine Daily Inquirer. Retrieved on 2006-10-07.
33.^ Dengue fever: Essential data. Chemical and Biological Warfare Agents. Retrieved on 2007-11-30
34.^ Dengue. Online Etymology Dictionary. Retrieved on 2007-11-30
35.^ "etymologia: dengue" (PDF) (2006). Emerging Infectious Diseases 12: 893.
36.^ Gubler DJ (1998). "Dengue and dengue hemorrhagic fever". Clin. Microbiol. Rev. 11 (3): 480–96. PMID 9665979.
[edit] References
Manson's Tropical Diseases
Mandell's Principles and Practices of Infection Diseases
Cecil Textbook of Medicine
The Oxford Textbook of Medicine
Harrison's Principles of Internal Medicine
Theiler, Max and Downs, W. G. 1973. The Arthropod-Borne Viruses of Vertebrates: An Account of The Rockefeller Foundation Virus Program 1951-1970. Yale University Press.
Downs, Wilbur H., et al. 1965. Virus diseases in the West Indies. Special edition of the Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, 1965.
Earle, k. Vigors. 1965. "Notes on the Dengue epidemic at Point Fortin." The Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, pp. 157-164.
Hill, A. Edward. 1965. "Isolation of Dengue Virus from a Human Being in Trinidad." Virus diseases in the West Indies. The Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, pp. 83-84; "Dengue and Related Fevers in Trinidad and Tobago." Ibid, pp. 91-96.
http://en.wikipedia.org/wiki/Tuberculosis
Tuberculosis
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Tuberculosis
Classification and external resources
Chest X-ray of a patient suffering from tuberculosis
ICD-10
A15.-A19.
ICD-9
010-018
OMIM
607948
DiseasesDB
8515
MedlinePlus
000077 000624
eMedicine
med/2324 emerg/618 radio/411
MeSH
C01.252.410.040.552.846
Tuberculosis (abbreviated as TB for tubercle bacillus or Tuberculosis) is a common and often deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti also cause tuberculosis, but these species are less common.
The typical symptoms of tuberculosis are a chronic cough with blood-tinged sputum, fever, night sweats and weight loss. Infection of other organs cause a wide range of symptoms. The diagnosis relies on radiology (commonly chest X-rays), a tuberculin skin test, blood tests, as well as microscopic examination and microbiological culture of bodily fluids. Tuberculosis treatment is difficult and requires long courses of multiple antibiotics. Contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in (extensively) multi-drug-resistant tuberculosis. Prevention relies on screening programs and vaccination, usually with Bacillus Calmette-Guérin (BCG vaccine).
Tuberculosis is spread through the air, when people who have the disease cough, sneeze or spit. One third of the world's current population have been infected with M. tuberculosis, and new infections occur at a rate of one per second.[1] However, most of these cases will not develop the full-blown disease; asymptomatic, latent infection is most common. About one in ten of these latent infections will eventually progress to active disease, which, if left untreated, kills more than half of its victims. In 2004, mortality and morbidity statistics included 14.6 million chronic active cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries.[1] In addition, a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or AIDS.
Contents
[hide]
1 Other names
2 Symptoms
3 Bacterial species
3.1 Evolution
4 Transmission
5 Pathogenesis
6 Diagnosis
7 Progression
8 Treatment
9 Prevention
9.1 Vaccines
10 Epidemiology
11 History
11.1 Folklore
11.2 Study and treatment
12 Infection of other animals
13 See also
14 References
15 Further reading
16 External links
[edit] Other names
In the past, tuberculosis has been called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names included phthisis (Greek for consumption) and phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king's evil, because it was believed that a king's touch would heal scrofula; and Pott's disease, or gibbus of the spine and joints.[2][3] Miliary tuberculosis—now commonly known as disseminated TB—occurs when the infection invades the circulatory system resulting in lesions which have the appearance of millet seeds on X-ray.[2][4]
[edit] Symptoms
Further information: Tuberculosis classification
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.[1]
In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB. This occurs more commonly 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.[5]
[edit] Bacterial species
Main article: Mycobacterium tuberculosis
Scanning electron micrograph of Mycobacterium tuberculosis
The primary cause of TB, Mycobacterium tuberculosis, is an aerobic bacterium that divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.[6] (For example, one of the fastest-growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolic acid content of its cell wall.[7] MTB is a small rod-like bacillus that can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in vitro.[8]
Using histological stains on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).[7] The most common staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include an auramine-rhodamine stain and fluorescent microscopy.
The M. tuberculosis complex includes three other TB-causing mycobacteria: M. bovis, M. africanum and M. microti. M. africanum is a not wiespread, but in parts of Africa it is a significant cause of tuberculosis.[9][10] 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.[11] M. microti is mostly seen in immunodeficient people, although it is possible that the prevalence of this pathogen has been underestimated.[12]
Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium avium and M. kansasii. The last two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.[13]
Phylogenetic tree of the genus Mycobacterium.
[edit] Evolution
Tuberculosis has co-evolved with humans for many thousands of years, and perhaps as much as several million years.[14] During this evolution, M. tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that M. tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain.[15]
[edit] Transmission
Further information: Transmission (medicine)
When people suffering from active pulmonary TB cough, sneeze, speak, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze, for instance, can release up to 40,000 droplets.[16] Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and the inhalation of just a single bacterium can cause a new infection.[17]
People with prolonged, frequent, or intense contact are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year.[1] Others at risk include people in areas where TB is common, people who inject drugs using unsanitary needles, residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.[18]
Transmission can only occur from people with active—not latent—TB. The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.[5] The chain of transmission can therefore be broken by isolating patients with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious. If someone does become infectous, then it will take at least from 21 days, or 3–4 weeks, before the new infectous person can transmit the disease to others.[19] TB can also be transmitted by eating meat if the cattle is infected with TB. Mycobacterium bovis causes TB in cattle. Details below.
[edit] Pathogenesis
Mycobacterium tuberculosis (stained red) in sputum
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%.[20]
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within alveolar macrophages.[21] 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 other tissues and organs where secondary TB lesions can develop in other parts of the lung, peripheral lymph nodes, kidneys, brain, and bone.[22] All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.[23]
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.[24] T lymphocytes (CD8+) can also directly kill infected cells.[21]
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.[25]
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.[26]
In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis.[25] 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.[25]
[edit] Diagnosis
For more details on this topic, see Tuberculosis diagnosis.
Mantoux tuberculin skin test
Tuberculosis can be a difficult disease to diagnose, mainly due to the difficulty in culturing this slow-growing organism in the laboratory (4–12 weeks for blood culture). 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.[5]
Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to an extract made from 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, so the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.[27] 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.[28] These tests are not affected by immunization, so generate fewer false positive results.[29] Rapid and inexpensive diagnosis will be particularly valuable in the developing world.
[edit] Progression
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—1–5% of cases—this occurs soon after infection. However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2–23% of these latent cases, often many years after infection.[30] 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.[20]
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.[5]
Twin studies in the 1950s showed that the course of TB infection was highly dependent on genetics. At that time, it was rare that one identical twin would die and the other live.[31]
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.[32]
[edit] Treatment
For more details on this topic, see Tuberculosis 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.[5] 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.[33] People with 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.[34]
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.[33] 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 (MDR-TB) is defined as resistance to the two most effective first line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.[35]
In ancient times, available treatments focused more on dietary parameters. Pliny the Elder described several methods in his Natural History: "wolf's liver taken in thin wine, the lard of a sow that has been fed upon grass, or the flesh of a she-ass taken in broth".[36] While these particular remedies haven't been tested scientifically, it has been demonstrated that malnourished mice receiving a 2% protein diet suffer far higher mortality from tuberculosis than those receiving 20% protein receiving the same infectious challenge dose, and the progressively fatal course of the illness could be reversed by restoring the mice to the normal diet.[37] Moreover, statistics for immigrants in South London reveal an 8.5 fold increased risk of tuberculosis in (primarily Hindu Asian) lacto vegetarians, who frequently suffer protein malnutrition, compared to those of similar cultural backgrounds who ate meat and fish daily.[38]
[edit] 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 levels of other species of mycobacteria are high, exposure to nontuberculous mycobacteria gives some protection against TB.[39]
The World Health Organization (W.H.O.) declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between 2006 and 2015.[40] Since humans are the only host of Mycobacterium tuberculosis, eradication would be possibile: a goal that would be helped greatly by an effective vaccine.[41]
[edit] Vaccines
Many countries use Bacillus Calmette-Guérin (BCG) vaccine as part of their TB control programs, especially for infants. According to the W.H.O., this is the most often used vaccine worldwide, with 85% of infants in 172 countries immunized in 1993.[42] This was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921.[43] However, mass vaccination with BCG did not start until after World War II.[44] 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%.[45]
In South Africa, the country with the highest prevalence of TB, BCG is given to all children under age three.[46] However, BCG is less effective in areas where mycobacteria are less prevalent; therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:[5]
Infants or children with negative skin test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.
BCG provides some protection against severe forms of pediatric TB, but has been shown to be unreliable against adult pulmonary TB, which accounts for most of the disease burden worldwide. Currently, there are more cases of TB on the planet than at any other time in history and most agree there is an urgent need for a newer, more effective vaccine that would prevent all forms of TB—including drug resistant strains—in all age groups and among people with HIV.[47]
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).[48] 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.[49] A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University,[50] and is based on a genetically modified vaccinia virus. Many other strategies are also being used to develop novel vaccines. In order to encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.[51][52]
The Bill and Melinda Gates Foundation has been a strong supporter of new TB vaccine development. Most recently, they announced a $200 million grant to the Aeras Global TB Vaccine Foundation for clinical trials on up to six different TB vaccine candidates currently in the pipeline.[53]
[edit] Epidemiology
Annual number of new reported TB cases. Data from WHO.[54]
World TB incidence. Cases per 100,000; Red = >300, orange = 200–300; yellow = 100–200; green 50–100; blue = <50 and grey = n/a. Data from WHO, 2006.[54]
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.[55] Annually, 8 million people become ill with tuberculosis, and 2 million people die from the disease worldwide.[56] 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.[1] Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS.[57]
The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.[58] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.[35] The rate at which new TB cases occur varies widely, even in neighboring countries, apparently because of differences in health care systems.[59]
In 2005, the country with the highest estimated incidence of TB was Swaziland, with 1262 cases per 100,000 people. India has the largest number of infections, with over 1.8 million cases.[60] 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;[61] 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.[56]
The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults.[62] However, in countries where TB has gone from high to low incidence, such as the United States, TB is mainly a disease of older people.[63]
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.[54][64] Smoking more than 20 cigarettes a day also increases the risk of TB by two to four times.[65][66] Diabetes mellitus is also an important risk factor that is growing in importance in developing countries.[67]
[edit] History
Tubercular decay has been found in the spines of Egyptian mummies. Pictured: Egyptian mummy in the British Museum
Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 18,000 years before the present.[68] Whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor infecting a different species, is currently unclear.[69] However, it is clear that M. tuberculosis is not directly descended from M. bovis, which seems to have evolved relativlely recently.[70]
Skeletal remains show prehistoric humans (4000 BC) had TB, and tubercular decay has been found in the spines of mummies from 3000–2400 BC.[71] Phthisis is a Greek term for tuberculosis; around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal.[72] Genetic studies suggest that TB was present in South America for about 2,000 years.[73] In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BC to circa 100 AD).[74]
[edit] Folklore
Before the Industrial Revolution, tuberculosis may sometimes have been regarded as vampirism. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that this was caused by the original victim draining the life from the other family members. Furthermore, people who had TB exhibited symptoms similar to what people considered to be vampire traits. People with TB often have symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin, extremely low body heat, a weak heart and coughing blood, suggesting the idea that the only way for the afflicted to replenish this loss of blood was by sucking blood.[75] Another folk belief attributed it to being forced, nightly, to attend fairy revels, so that the victim wasted away owing to lack of rest; this belief was most common when a strong connection was seen between the fairies and the dead.[76] Similarly, but less commonly, it was attributed to the victims being "hagridden"—being transformed into horses by witches (hags) to travel to their nightly meetings, again resulting in a lack of rest.[76]
TB was romanticized in the nineteenth century. Many people believed TB produced feelings of euphoria referred to as "Spes phthisica" or "hope of the consumptive". It was believed that TB sufferers who were artists had bursts of creativity as the disease progressed. It was also believed that TB sufferers acquired a final burst of energy just before they died which made women more beautiful and men more creative.[77] In the early 20th century, some believed TB to be caused by masturbation.[78]
[edit] Study and treatment
The study of tuberculosis dates back to The Canon of Medicine written by Ibn Sina (Avicenna) in the 1020s. He was the first physician to identify pulmonary tuberculosis as a contagious disease, the first to recognise the association with diabetes, and the first to suggest that it could spread through contact with soil and water.[79][80] He developed the method of quarantine in order to limit the spread of tuberculosis.[81]
Although it was established that the pulmonary form was associated with 'tubercles' by Dr Richard Morton in 1689,[82][83] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s and was not named 'tuberculosis' until 1839 by J. L. Schönlein.[84] During the years 1838–1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers into the cave in the hope of curing the disease with the constant temperature and purity of the cave air: they died within a year.[85] The first TB sanatorium opened in 1859 in Görbersdorf, Germany (today Sokolowsko, Poland) by Hermann Brehmer.[86]
In regard to this claim, The Times for January 15, 1859, page 5, column 5, carries an advertisement seeking funds for the Bournemouth Sanatorium for Consumption, referring to the balance sheet for the past year, and offering an annual report to prospective donors, implying that this sanatorium was in existence at least in 1858.
Dr. Robert Koch discovered the tuberculosis bacilli.
The bacillus causing tuberculosis, Mycobacterium tuberculosis, was identified and described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery.[87] Koch did not believe that bovine (cattle) and human tuberculosis were similar, which delayed the recognition of infected milk as a source of infection. Later, this source was eliminated by the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it 'tuberculin'. It was not effective, but was later adapted as a test for pre-symptomatic tuberculosis.[88]
The first genuine success in immunizing against tuberculosis was developed from attenuated bovine-strain tuberculosis by Albert Calmette and Camille Guérin in 1906. It was called "BCG" (Bacillus of Calmette and Guérin). The BCG vaccine was first used on humans in 1921 in France,[43] but it was not until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany.[44]
Tuberculosis, or "consumption" as it was commonly known, caused the most widespread public concern in the 19th and early 20th centuries as an endemic disease of the urban poor. In 1815, one in four deaths in England was of consumption; by 1918 one in six deaths in France were still caused by TB. In the 20th century, tuberculosis killed an estimated 100 million people.[89] After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons; the sanatoria for the middle and upper classes offered excellent care and constant medical attention.[86] Whatever the purported benefits of the fresh air and labor in the sanatoria, even under the best conditions, 50% of those who entered were dead within five years (1916).[86]
Public health campaigns tried to halt the spread of TB
The promotion of Christmas Seals began in Denmark during 1904 as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907–08 to help the National Tuberculosis Association (later called the American Lung Association).
In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.
In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease remained a significant threat to public health, such that when the Medical Research Council was formed in Britain in 1913 its initial focus was tuberculosis research.[90]
It was not until 1946 with the development of the antibiotic streptomycin that effective treatment and cure became possible. Prior to the introduction of this drug, the only treatment besides sanatoria were surgical interventions, including the pneumothorax technique—collapsing an infected lung to "rest" it and allow lesions to heal—a technique that was of little benefit and was largely discontinued by the 1950s.[91] The emergence of multidrug-resistant TB has again introduced surgery as part of the treatment for these infections. Here, surgical removal of chest cavities will reduce the number of bacteria in the lungs, as well as increasing the exposure of the remaining bacteria to drugs in the bloodstream, and is therefore thought to increase the effectiveness of the chemotherapy.[92]
Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, tuberculosis cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases rose again, reaching 6,300 in 2000 and 7,600 cases in 2005.[93] Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence in the late 1980s.[94] The number of those failing to complete their course of drugs is high. NY had to cope with more than 20,000 "unnecessary" TB-patients with multidrug-resistant strains (resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.[95]
[edit] Infection of other animals
Main article: Mycobacterium bovis
Tuberculosis can be carried by mammals; domesticated species, such as cats and dogs, are generally free of tuberculosis, but wild animals may be carriers. In some places, regulations aiming to prevent the spread of TB restrict the ownership of novelty pets; for example, the U.S. state of California forbids the ownership of pet gerbils.[96]
Mycobacterium bovis causes TB in cattle. An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is underway. It has been found that herd infection is more likely in areas where infected vector species such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders.[97] Controlling the vectors through possum eradication and monitoring the level of disease in livestock herds through regular surveillance are seen as a "two-pronged" approach to ridding New Zealand of the disease.
In the Republic of Ireland and the United Kingdom, badgers have been identified as one vector species for the transmission of bovine tuberculosis. As a result, governments have come under pressure from some quarters, primarily dairy farmers, to mount an active campaign of eradication of badgers in certain areas with the purpose of reducing the incidence of bovine TB. The effectiveness of culling on the incidence of TB in cattle is a contentious issue, with proponents and opponents citing their own studies to support their position.[98][99][100] For instance, a study by an Independent Study Group on badger culling reported on 18 June 2007 that it was unlikely to be effective and would only make a "modest difference" to the spread of TB and that "badger culling cannot meaningfully contribute to the future control of cattle TB"; in contrast, another report concluded that this policy would have a significant impact.[101] On July 4th 2008, the UK government decided against a proposed random culling policy.[102]
[edit] See also
2007 tuberculosis scare
Abreugraphy
ATC code J04 Drugs for treatment of TB
Buruli ulcer and leprosy: other diseases caused by mycobacteria
Latent tuberculosis
List of tuberculosis victims
Mycobacterium Tuberculosis Structural Genomics Consortium
National Center for HIV, STD, and TB Prevention
Nontuberculous mycobacteria
Overcrowding
Philip D'Arcy Hart
The Global Fund to Fight AIDS, Tuberculosis and Malaria
Tuberculosis in history and art
UNITAID
Nosocomial infection
[edit] References
1.^ a b c d e World Health Organization (WHO). Tuberculosis Fact sheet N°104 - Global and regional incidence. March 2006, Retrieved on 6 October 2006.
2.^ a b Tuberculosis Encyclopedia Britannica, 11th ed.
3.^ Rudy's List of Archaic Medical Terms English Glossary of Archaic Medical Terms, Diseases and Causes of Death. Accessed 9 October 2006
4.^ Disseminated tuberculosis NIH Medical Encyclopedia. Accessed 9 October 2006
5.^ a b c d e f Centers for Disease Control and Prevention (CDC), Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis: What the Clinician Should Know. 4th edition (2000). Updated August 2003.
6.^ Cox R (2004). "Quantitative relationships for specific growth rates and macromolecular compositions of Mycobacterium tuberculosis, Streptomyces coelicolor A3(2) and Escherichia coli B/r: an integrative theoretical approach". Microbiology 150 (Pt 5): 1413–26. doi:10.1099/mic.0.26560-0. PMID 15133103.
7.^ a b Madison B (2001). "Application of stains in clinical microbiology". Biotech Histochem 76 (3): 119–25. doi:10.1080/714028138. PMID 11475314.
8.^ Parish T, Stoker N (1999). "Mycobacteria: bugs and bugbears (two steps forward and one step back)". Mol Biotechnol 13 (3): 191–200. doi:10.1385/MB:13:3:191. PMID 10934532.
9.^ Niemann S, Rüsch-Gerdes S, Joloba ML, et al (September 2002). "Mycobacterium africanum subtype II is associated with two distinct genotypes and is a major cause of human tuberculosis in Kampala, Uganda". J. Clin. Microbiol. 40 (9): 3398–405. PMID 12202584. PMC:130701.
10.^ Niobe-Eyangoh SN, Kuaban C, Sorlin P, et al (June 2003). "Genetic biodiversity of Mycobacterium tuberculosis complex strains from patients with pulmonary tuberculosis in Cameroon". J. Clin. Microbiol. 41 (6): 2547–53. PMID 12791879. PMC:156567.
11.^ Thoen C, Lobue P, de Kantor I (February 2006). "The importance of Mycobacterium bovis as a zoonosis". Vet. Microbiol. 112 (2-4): 339–45. doi:10.1016/j.vetmic.2005.11.047. PMID 16387455.
12.^ Niemann S, Richter E, Dalügge-Tamm H, Schlesinger H, Graupner D, Königstein B, Gurath G, Greinert U, Rüsch-Gerdes S (2000). "Two cases of Mycobacterium microti derived tuberculosis in HIV-negative immunocompetent patients". Emerg Infect Dis 6 (5): 539–42. PMID 10998387.
13.^ "Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association" (1997). Am J Respir Crit Care Med 156 (2 Pt 2): S1–25. PMID 9279284.
14.^ Gutierrez MC, Brisse S, Brosch R, et al (September 2005). "Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis". PLoS Pathog. 1 (1): e5. doi:10.1371/journal.ppat.0010005. PMID 16201017. PMC:1238740.
15.^ Rao K, Kauser F, Srinivas S, Zanetti S, Sechi L, Ahmed N, Hasnain S (2005). "Analysis of genomic downsizing on the basis of region-of-difference polymorphism profiling of Mycobacterium tuberculosis patient isolates reveals geographic partitioning". J Clin Microbiol 43 (12): 5978–82. doi:10.1128/JCM.43.12.5978-5982.2005. PMID 16333085.
16.^ Cole E, Cook C (1998). "Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies". Am J Infect Control 26 (4): 453–64. doi:10.1016/S0196-6553(98)70046-X. PMID 9721404.
17.^ Nicas M, Nazaroff WW, Hubbard A (2005). "Toward understanding the risk of secondary airborne infection: emission of respirable pathogens". J Occup Environ Hyg 2 (3): 143–54. doi:10.1080/15459620590918466. PMID 15764538.
18.^ Griffith D, Kerr C (1996). "Tuberculosis: disease of the past, disease of the present". J Perianesth Nurs 11 (4): 240–5. doi:10.1016/S1089-9472(96)80023-2. PMID 8964016.
19.^ "Causes of Tuberculosis". Mayo Clinic (2006-12-21). Retrieved on 2007-10-19.
20.^ a b Onyebujoh, Phillip and Rook, Graham A. W. World Health Organization Disease Watch: Focus: Tuberculosis. December 2004. Accessed 7 October 2006.
21.^ a b Houben E, Nguyen L, Pieters J (2006). "Interaction of pathogenic mycobacteria with the host immune system". Curr Opin Microbiol 9 (1): 76–85. doi:10.1016/j.mib.2005.12.014. PMID 16406837.
22.^ Herrmann J, Lagrange P (2005). "Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse?". Pathol Biol (Paris) 53 (1): 35–40. PMID 15620608.
23.^ Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D (2005). "Tuberculous dilated cardiomyopathy: an under-recognized entity?". BMC Infect Dis 5 (1): 29. doi:10.1186/1471-2334-5-29. PMID 15857515.
24.^ Kaufmann S (2002). "Protection against tuberculosis: cytokines, T cells, and macrophages". Ann Rheum Dis 61 Suppl 2: ii54–8. PMID 12379623.
25.^ a b c Grosset J (2003). "Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary". Antimicrob Agents Chemother 47 (3): 833–6. doi:10.1128/AAC.47.3.833-836.2003. PMID 12604509.
26.^ Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B (2003). "Miliary tuberculosis and acute respiratory distress syndrome". Int J Tuberc Lung Dis 7 (4): 359–64. PMID 12733492.
27.^ Rothel J, Andersen P (2005). "Diagnosis of latent Mycobacterium tuberculosis infection: is the demise of the Mantoux test imminent?". Expert Rev Anti Infect Ther 3 (6): 981–93. doi:10.1586/14787210.3.6.981. PMID 16307510.
28.^ Nahid P, Pai M, Hopewell P (2006). "Advances in the diagnosis and treatment of tuberculosis". Proc Am Thorac Soc 3 (1): 103–10. doi:10.1513/pats.200511-119JH. PMID 16493157.
29.^ Pai M, Zwerling A, Menzies D (June 2008). "Systematic Review: T-Cell-Based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update". Ann. Intern. Med. 149 (3): 1-9. PMID 18593687.
30.^ Parrish N, Dick J, Bishai W (1998). "Mechanisms of latency in Mycobacterium tuberculosis". Trends Microbiol 6 (3): 107–12. doi:10.1016/S0966-842X(98)01216-5. PMID 9582936.
31.^ New Scientist, 16 June 2007 [1]
32.^ Mutlu G, Mutlu E, Bellmeyer A, Rubinstein I (2006). "Pulmonary adverse events of anti-tumor necrosis factor-alpha antibody therapy". Am J Med 119 (8): 639–46. doi:10.1016/j.amjmed.2006.01.015. PMID 16887405.
33.^ a b O'Brien R (1994). "Drug-resistant tuberculosis: etiology, management and prevention". Semin Respir Infect 9 (2): 104–12. PMID 7973169.
34.^ "Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003" (2003). MMWR Morb Mortal Wkly Rep 52 (31): 735–9. PMID 12904741.
35.^ a b "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004" (2006). MMWR Morb Mortal Wkly Rep 55 (11): 301–5. PMID 16557213.
36.^ Pliny the Elder, Natural History, quoted at Naphtali Lewis, Meyer Reinhold. "Roman Civilization".
37.^ John Chan, Yu Tian, Kathryn E. Tanakadagger, Ming S. Tsang, Keming Yu, Padmini Salgame, Dinah Carroll, Yvonne Kress, Rachel Teitelbaum, and Barry R. Bloom (1996-12-10). "Effects of protein calorie malnutrition on tuberculosis in mice". Proc Natl Acad Sci U S A 93 (25): 14857–61. doi:10.1073/pnas.93.25.14857. PMID 8962145.
38.^ Strachan DP, Powell KJ, Thaker A, Millard FJ, Maxwell JD (1995-02). "Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians". Thorax 50 (2): 175–80. PMID 8962145.
39.^ Fine P, Floyd S, Stanford J, Nkhosa P, Kasunga A, Chaguluka S, Warndorff D, Jenkins P, Yates M, Ponnighaus J (2001). "Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy". Epidemiol Infect 126 (3): 379–87. doi:10.1017/S0950268801005532. PMID 11467795.
40.^ World Health Organization (WHO). Stop TB Partnership. Retrieved on 3 October 2006.
41.^ Martin C (May 2006). "Tuberculosis vaccines: past, present and future". Curr Opin Pulm Med 12 (3): 186–91. doi:10.1097/01.mcp.0000219267.27439.1b. PMID 16582673.
42.^ WHO statement on BCG revaccination for the prevention of tuberculosis. Geneva: World Health Organization; 1995.
43.^ a b Bonah C (2005). "The 'experimental stable' of the BCG vaccine: safety, efficacy, proof, and standards, 1921–1933". Stud Hist Philos Biol Biomed Sci 36 (4): 696–721. doi:10.1016/j.shpsc.2005.09.003. PMID 16337557.
44.^ a b Comstock G (1994). "The International Tuberculosis Campaign: a pioneering venture in mass vaccination and research". Clin Infect Dis 19 (3): 528–40. PMID 7811874.
45.^ Bannon M (1999). "BCG and tuberculosis". Arch Dis Child 80 (1): 80–3. PMID 10325767.
46.^ WHO/UNICEF Review of National Immunization Coverage 1980–2005: South Africa (PDF). World Health Organization (August 2006). Retrieved on 2007-06-08.
47.^ Sadoff, Jerry. Advances in Tuberculosis Vaccine Strategies. Nature Reviews Microbiology. Vol. 4. June 2006.
48.^ National Institute of Allergy and Infectious Diseases (NIAID).First U.S. Tuberculosis Vaccine Trial in 60 Years Begins. National Institutes of Health News 26 January 2004. Retrieved on 19 October 2007.
49.^ Ha S, Jeon B, Youn J, Kim S, Cho S, Sung Y (2005). "Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis". Gene Ther 12 (7): 634–8. doi:10.1038/sj.gt.3302465. PMID 15690060.
50.^ Ibanga H, Brookes R, Hill P, Owiafe P, Fletcher H, Lienhardt C, Hill A, Adegbola R, McShane H (2006). "Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design". Lancet Infect Dis 6 (8): 522–8. doi:10.1016/S1473-3099(06)70552-7. PMID 16870530.
51.^ Webber, David and Kremer, Michael. Stimulating Industrial R&D for Neglected Infectious Diseases: Economic Perspectives (PDF). Bulletin of the World Health Organization 79(8), 2001, pp. 693–801.
52.^ Barder, Owen; Kremer, Michael; Williams, Heidi. "Advance Market Commitments: A Policy to Stimulate Investment in Vaccines for Neglected Diseases," The Economists' Voice, Vol. 3 (2006) Issue 3.
53.^ Aeras Receives New Grant from the Gates Foundation
54.^ a b c World Health Organization (WHO). Global tuberculosis control - surveillance, planning, financing WHO Report 2006. Retrieved on 13 October 2006.
55.^ National Institute of Allergy and Infectious Diseases (NIAID). [2] 26 October 2005. Retrieved on 3 October 2006. "According to the World Health Organization (WHO), nearly 2 billion people, one-third of the world's population, have TB."
56.^ a b Centers for Disease Control. Fact Sheet: Tuberculosis in the United States. 17 March 2005, Retrieved on 6 October 2006.
57.^ Stop TB Partnership. London tuberculosis rates now at Third World proportions. PR Newswire Europe Ltd. 4 December 2002. Retrieved on 3 October 2006.
58.^ Iademarco MF, Castro KG (2003). "Epidemiology of tuberculosis". Seminars in respiratory infections 18 (4): 225–40. doi:10.1017/S0950268801005532. PMID 14679472.
59.^ Sobero R, Peabody J (2006). "Tuberculosis control in Bolivia, Chile, Colombia and Peru: why does incidence vary so much between neighbors?". Int J Tuberc Lung Dis 10 (11): 1292–5. PMID 17131791.
60.^ Global tuberculosis control: surveillance, planning, financing. WHO report 2007. Geneva, World Health Organization (WHO/HTM/TB/2007.376)
61.^ Notification rates of tuberculosis: by NHS Regional Office area, 1990-2001: Regional Trends 37 Office for National Statistics Retrieved on 13 October 2006.
62.^ World Health Organization (WHO). Global Tuberculosis Control Report, 2006 - Annex 1 Profiles of high-burden countries. (PDF) Retrieved on 13 October 2006.
63.^ Centers for Disease Control and Prevention (CDC). 2005 Surveillance Slide Set. (September 12, 2006) Retrieved on 13 October 2006.
64.^ Chaisson RE, Martinson NA (2008). "Tuberculosis in Africa—combating an HIV-driven crisis". N Engl J Med 358 (11): 1089–1092. doi:10.1056/NEJMp0800809. PMID 18337598.
65.^ Davies PDO, Yew WW, Ganguly D, et al. (2006). "Smoking and tuberculosis: the epidemiological association and pathogenesis". Trans R Soc Trop Med Hyg 100: 291–8. doi:10.1016/j.trstmh.2005.06.034. PMID 16325875.
66.^ Jha P, Jacob B, Gajalakshmi V, et al. (2008). "A nationally representative case–control study of smoking and death in India". N Engl J Med 358 (11): 1137–1147. doi:10.1056/NEJMsa0707719. PMID 18272886.
67.^ Restrepo BI (2007). "Convergence of the tuberculosis and diabetes epidemics: renewal of old acquaintances" ([dead links] – Scholar search). Clin Infect Dis 45: 436–8. doi:10.1086/519939.
68.^ Rothschild B, Martin L, Lev G, Bercovier H, Bar-Gal G, Greenblatt C, Donoghue H, Spigelman M, Brittain D (2001). "Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present". Clin Infect Dis 33 (3): 305–11. doi:10.1086/321886. PMID 11438894.
69.^ Pearce-Duvet J (2006). "The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease". Biol Rev Camb Philos Soc 81 (3): 369–82. doi:10.1017/S1464793106007020. PMID 16672105.
70.^ Ernst JD, Trevejo-Nuñez G, Banaiee N (July 2007). "Genomics and the evolution, pathogenesis, and diagnosis of tuberculosis". J. Clin. Invest. 117 (7): 1738–45. doi:10.1172/JCI31810. PMID 17607348. PMC:1904327.
71.^ Zink A, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich A (2003). "Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping". J Clin Microbiol 41 (1): 359–67. doi:10.1128/JCM.41.1.359-367.2003. PMID 12517873.
72.^ Hippocrates. Aphorisms. Accessed 7 October 2006.
73.^ Konomi N, Lebwohl E, Mowbray K, Tattersall I, Zhang D (2002). "Detection of mycobacterial DNA in Andean mummies". J Clin Microbiol 40 (12): 4738–40. doi:10.1128/JCM.40.12.4738-4740.2002. PMID 12454182.
74.^ "South America: Prehistoric Findings". Memorias do Instituto Oswaldo Cruz, Vol. 98 (Suppl.I) January 2003. Retrieved on 2007-02-08.
75.^ Sledzik P, Bellantoni N (1994). "Brief communication: bioarcheological and biocultural evidence for the New England vampire folk belief". Am J Phys Anthropol 94 (2): 269–74. doi:10.1002/ajpa.1330940210. PMID 8085617.
76.^ a b Katharine Briggs, An Encyclopedia of Fairies "Consumption" (Pantheon Books, 1976) p. 80. ISBN 0-394-73467-X
77.^ Lawlor, Clark. "Transatlantic Consumptions: Disease, Fame and Literary Nationalism in the Davidson Sisters, Southey, and Poe". Studies in the Literary Imagination, Fall 2003. Available at findarticles.com. Retrieved on 2007-06-08.
78.^ Laumann, Edward O. (1994) The Social Organization of Sexuality: Sexual Practices in the United States University of Chicago Press p 80, ISBN 0-22647-020-2
79.^ Y. A. Al-Sharrah (2003), "The Arab Tradition of Medical Education and its Relationship with the European Tradition", Prospects 33 (4), Springer.
80.^ George Sarton, Introduction to the History of Science.
(cf. Dr. A. Zahoor and Dr. Z. Haq (1997). Quotations From Famous Historians of Science, Cyberistan.)
81.^ David W. Tschanz, MSPH, PhD (August 2003). "Arab Roots of European Medicine", Heart Views 4 (2).
82.^ Who Named It? Léon Charles Albert Calmette. Retrieved on 6 October 2006.
83.^ Trail R (1970). "Richard Morton (1637–1698)". Med Hist 14 (2): 166–74. PMID 4914685.
84.^ Zur Pathogenie der Impetigines. Auszug aus einer brieflichen Mitteilung an den Herausgeber. [Müller's] Archiv für Anatomie, Physiologie und wissenschaftliche Medicin. 1839, page 82.
85.^ Kentucky: Mammoth Cave long on history. CNN. 27 February 2004. Accessed 8 October 2006.
86.^ a b c McCarthy OR (2001). "The key to the sanatoria". J R Soc Med 94 (8): 413–7. PMID 11461990.
87.^ Nobel Foundation. The Nobel Prize in Physiology or Medicine 1905. Accessed 7 October 2006.
88.^ Waddington K (2004). "To stamp out "so terrible a malady": bovine tuberculosis and tuberculin testing in Britain, 1890–1939". Med Hist 48 (1): 29–48. PMID 14968644.
89.^ Torrey EF and Yolken RH. 2005. Their bugs are worse than their bite. Washington Post, April 3, p. B01.
90.^ Medical Research Council (UK). MRC's contribution to Tuberculosis research. Accessed 2 July 2007.
91.^ Wolfart W (1990). "Surgical treatment of tuberculosis and its modifications—collapse therapy and resection treatment and their present-day sequelae". Offentl Gesundheitswes 52 (8–9): 506–11. PMID 2146567.
92.^ Lalloo U, Naidoo R, Ambaram A (2006). "Recent advances in the medical and surgical treatment of multi-drug resistant tuberculosis". Curr Opin Pulm Med 12 (3): 179–85. doi:10.1097/01.mcp.0000219266.27439.52. PMID 16582672.
93.^ "Tuberculosis – Respiratory and Non-respiratory Notifications, England and Wales, 1913-2005". Health Protection Agency Centre for Infections (21 March 2007). Retrieved on 2007-08-01.
94.^ Paolo W, Nosanchuk J (2004). "Tuberculosis in New York city: recent lessons and a look ahead". Lancet Infect Dis 4 (5): 287–93. doi:10.1016/S1473-3099(04)01004-7. PMID 15120345.
95.^ World Health Organization (WHO). Frequently asked questions about TB and HIV. Retrieved 6 October 2006.
96.^ 14 CA ADC § 671 Barclays official California code of regulations; Title 14. Natural resources; Division 1. Fish and game commission – Department of fish and game; Subdivision 3. General regulations; Chapter 3. Miscellaneous.
97.^ Tweddle N, Livingstone P (1994). "Bovine tuberculosis control and eradication programs in Australia and New Zealand". Vet Microbiol 40 (1–2): 23–39. doi:10.1016/0378-1135(94)90044-2. PMID 8073626.
98.^ The Department of Agriculture & Food (Ireland). Disease Eradication Schemes - Bovine Tuberculosis and Brucellosis. Retrieved on 8 May 2006.
99.^ Cassidy, Martin. Badgers targeted over bovine TB. BBC News 2 December 2004. Retrieved on 8 May 2006.
100.^ National Federation of Badger Groups (Ireland). Cattle blamed for massive increase in bovine TB. Retrieved on 8 May 2006.
101.^ "Badgers and cattle TB: the final report of the Independent Scientific Group on Cattle TB". House of Commons Environment, Food and Rural Affairs Committee. Retrieved on 2008-07-04.
102.^ "Farmers' anger on cull rejection". BBC News (4 July 2008). Retrieved on 2008-07-04.
http://content.nejm.org/cgi/content/full/359/3/313
Artesunate for Malaria
To the Editor: Rosenthal (April 24 issue)1 presents a hypothetical case of malaria and states that there is "major concern" about the timeliness of artesunate availability because it is available rapidly only for hospitals that are near the 20 Centers for Disease Control and Prevention (CDC) quarantine stations. Artesunate is stocked at 8 of the 20 stations, which are located at major U.S. airports. To date, the timeliness of the provision of artesunate has been quite reasonable. Among the actual cases of the disease, on average it has taken only 7 hours (range, 3.5 to 15.5) from the time of the request for artesunate until the patient receives the first dose; 73% of the patients treated have been in hospitals that are not near CDC quarantine stations (average distance, 480 miles [772 km]; range, 66 to 1448 [106 to 2330]). To date, all patients treated according to this protocol have recovered. The CDC will continue to provide artesunate until it becomes a Food and Drug Administration (FDA)–approved, commercially available product and hospitals can maintain their own supply. Meanwhile, the current system can provide artesunate rapidly, and health care providers should be encouraged to access this medicine for the treatment of severe malaria.
Paul M. Arguin, M.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
Peter J. Weina, M.D., Ph.D.
Walter Reed Army Institute of Research
Silver Spring, MD 20910
Cindy P. Dougherty, Pharm.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
References
1.Rosenthal PJ. Artesunate for the treatment of severe falciparum malaria. N Engl J Med 2008;358:1829-1836. [Free Full Text]
http://content.nejm.org/cgi/content/full/358/17/1829?ijkey=d48a20305fe28c7c32c5471cea7f9dd4d96c0626&keytype2=tf_ipsecsha
Artesunate for the Treatment of Severe Falciparum Malaria
Philip J. Rosenthal, M.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author's clinical recommendations.
A previously well, American-born 35-year-old man presents with a 5-day history of fever and progressive dyspnea and a 2-day history of jaundice. An evaluation 3 days before his presentation led to a diagnosis of a viral syndrome. The patient had returned 3 weeks earlier from a 1-month stay in West Africa. He reports receiving immunizations before travel and taking pills to prevent malaria weekly until his return to the United States.
The physical examination shows moderate respiratory distress, diffuse pulmonary crackles, and mild jaundice. His vital signs include a temperature of 39.8°C, respiratory rate of 32 breaths per minute, and oxygen saturation of 87% while he is breathing ambient air. Abnormal results of laboratory tests include a hematocrit of 32.2%, platelet count of 78 per cubic millimeter, total bilirubin level of 4.2 mg per deciliter (71.8 µmol per liter), and creatinine level of 2.2 mg per deciliter (194.5 µmol per liter). A Giemsa-stained blood smear shows numerous ring forms of Plasmodium falciparum, with parasitemia estimated at 2%. He is immediately hospitalized, and an infectious-disease consultant recommends that the Centers for Disease Control and Prevention (CDC) be contacted to obtain intravenous artesunate for his treatment.
The Clinical Problem
Malaria is one of the most important infectious diseases in the world, causing hundreds of millions of illnesses and an estimated 1 million deaths each year.1 Malaria is endemic throughout most of the tropics, but it is most readily transmitted in sub-Saharan Africa. Nearly all serious illnesses and deaths from malaria are caused by P. falciparum.
Severe malaria, which is much less common than uncomplicated disease, is difficult to define precisely, especially in regions where malaria is endemic, because other serious illnesses can coexist with malarial infection. Severe malaria is generally defined as acute malaria with major signs of organ dysfunction or high levels of parasitemia (Table 1).2 In areas where malaria is endemic, young children are at high risk for severe malaria. Partial immunity develops in older children and adults after repeated infections, and they are thus at relatively low risk for severe disease. Pregnant women are also at increased risk for severe malaria.4
View this table:
[in this window]
[in a new window]
Table 1. Characteristics of Severe Malaria.
Travelers to areas where malaria is endemic often contract the disease, mostly because of lack of compliance with preventive measures such as the avoidance of night-biting anopheline mosquitoes and use of chemoprophylaxis. Travelers generally have no previous exposure to malaria parasites and so are at high risk for progression to severe disease if they are infected with P. falciparum.5 In a large survey of travel clinics, malaria was the most frequent cause of fever without localizing findings, and it was particularly common in febrile travelers returning from Africa.6 In recent years, approximately 1000 to 1600 episodes of malaria have been diagnosed each year in Americans after return from travel7; approximately 5 to 10% of these cases are estimated to meet criteria for severe malaria.8 Thus, although it is important to consider malaria in all febrile patients with a history of travel to areas where malaria is endemic, American physicians frequently do not do so. During the period from 1985 to 2001, the case fatality rate for P. falciparum infections in the United States was estimated at 1.3%, and delayed diagnosis contributed to poor outcomes in many cases.9
Pathophysiology and Effect of Therapy
When an infectious anopheline mosquito bites, it injects sporozoites, which circulate and invade hepatocytes (Figure 1). After asymptomatic hepatic infection (lasting 1 to 2 weeks in the case of P. falciparum infection), merozoites are released and invade erythrocytes. The asexual erythrocytic stage of infection is responsible for all clinical aspects of malaria. In erythrocytes, parasites develop into ring forms, mature trophozoites, and then multinucleated schizonts, which rupture and release more merozoites. Repeated cycles of erythrocyte invasion and rupture lead to chills, fever, headache, fatigue, other nonspecific symptoms, and, with severe malaria, signs of organ dysfunction (Table 1). Some parasites develop into gametocytes, which may be taken up by mosquitoes, in which sexual reproduction and further development of the parasites lead to the generation of a new set of infectious sporozoites.
View larger version (68K):
[in this window]
[in a new window]
Figure 1. Life Cycle of Plasmodium falciparum.
Elements that are important for the pathogenesis of severe malaria are shown. Erythrocytes containing P. falciparum in mature intraerythrocytic stages (trophozoites and schizonts) adhere to vascular endothelium, thereby avoiding clearance by the spleen. High numbers of circulating parasites and elaboration of host and parasite factors in the vasculature of various organs lead to the manifestations of severe malaria.
A key feature of the life cycle of P. falciparum is cytoadherence, whereby erythrocytes infected with mature parasites adhere to endothelial cells in the microvasculature.10 This process is presumably advantageous to the parasite, since it prevents the passage of abnormal erythrocytes through the spleen. High concentrations of P. falciparum–infected erythrocytes in the microvasculature and a complex interplay of host and parasite factors lead to the manifestations of severe malaria, including cerebral malaria, noncardiogenic pulmonary edema, and renal failure.11 Because of the ability of mature P. falciparum organisms in the erythrocytic stage to adhere to endothelial cells, only ring forms circulate (except in very severe infections), and levels of peripheral parasitemia may be quite low despite substantial infection.
Many drugs are available for the treatment of uncomplicated malaria (i.e., malaria that is not classified as severe).12,13 However, control in areas where malaria is endemic is limited by drug resistance, the toxic effects of some agents, and the relatively high cost and limited availability of newer drugs. Intravenous quinine and — in the United States — intravenous quinidine have been the standard therapies for severe cases of falciparum malaria for many years.
The most important new class of antimalarial agents is the artemisinins, which are natural products developed in China beginning in the 1960s.14 A number of artemisinin derivatives in addition to the parent compound are now available, including artesunate, artemether, artemotil, and dihydroartemisinin. Although the mechanisms of action of artemisinins are not fully understood, they may include free-radical production in the parasite food vacuole15 and inhibition of a parasite calcium ATPase.16 A key advantage of artemisinins is rapid action against all of the erythrocytic stages of the parasite, including transmissible gametocytes, resulting in a rapid clinical benefit and decreased transmission of malaria (Figure 1). In addition, there is currently limited, if any, resistance to artemisinins in malaria parasites. Although all artemisinins have rapid antiparasitic activity, they have short half-lives, such that the standard 3-day treatment course is commonly followed by recrudescence of infecting parasites and recurrent illness within days to weeks.14 To help prevent late recrudescences and the emergence of resistant parasites, these drugs should always be used in combination with a longer-acting agent. Fixed-dose combinations for oral therapy of uncomplicated malaria, known as artemisinin-based combination therapy, have been developed recently.
Clinical Evidence
When used correctly, chemoprophylaxis appears to be highly effective in preventing malaria.5 The drugs recommended by the CDC to prevent malaria in travelers to areas with drug-resistant falciparum malaria (i.e., most regions of the world where malaria is endemic) are mefloquine, atovaquone–proguanil, and doxycycline.5 In the vignette, the patient's weekly regimen was presumably mefloquine, but he apparently did not continue to receive the drug for 4 weeks after travel, as is required to eradicate parasites that emerge from the liver some weeks after exposure.
Treatment of malaria is generally highly effective when provided rapidly, used correctly, and not limited by drug resistance.12 Approved therapies for treatment of uncomplicated falciparum malaria in the United States include atovaquone–proguanil, quinine (a 3-day course plus a 1-week course of doxycycline or, in children, clindamycin), and mefloquine.17 For severe malaria, which is best treated intravenously, the only therapy available in the United States in recent years has been intravenous quinidine, which is generally highly efficacious. However, quinine and quinidine are associated with considerable toxic effects, including tinnitus, reversible hearing loss, nausea, vomiting, dizziness, hypoglycemia, and visual disturbances. As compared with quinine, intravenous quinidine is associated with greater risks of cardiotoxic effects and hypotension.18 The antimalarial efficacy of quinine has diminished in some areas, in particular Southeast Asia,19 suggesting partial resistance that may limit the drug's efficacy against severe malaria.
Artemisinin-based combination therapies, including artesunate–mefloquine, artemether–lumefantrine, artesunate–amodiaquine, and dihydroartemisinin–piperaquine, are highly efficacious,20,21,22,23,24,25 and they are now listed as first-line therapies for uncomplicated malaria in most countries where malaria is endemic. No artemisinin-based combination therapies are yet available in the United States. The rapid reduction in the level of parasitemia with the use of artemisinins has also led to interest in their use for the treatment of severe malaria. Intravenous and intramuscular artemisinins have been highly efficacious for the treatment of severe malaria. Rectal administration is also effective and may be of value in settings with limited resources.26
The first artemisinin to be studied in large clinical trials of severe malaria was artemether. Large randomized comparisons of intramuscular artemether and quinine in Gambian children27 and Vietnamese adults28 and a meta-analysis of individual data from 1919 patients in 11 trials of parenteral therapy29 identified no significant difference in efficacy between these agents. However, in the meta-analysis, the subgroup of adults had lower mortality when treated with artemether.
The efficacy of intramuscular artemether in severe malaria may be limited by varied absorption of this fat-soluble artemisinin derivative. Artesunate, which is water-soluble, has more reliable pharmacokinetic characteristics.30 A large, randomized comparison of intravenous artesunate and quinine in 1461 patients in Asia showed a significant survival benefit with artesunate. Mortality was 22% with quinine, as compared with 15% with artesunate, a risk reduction of 34.7%.31 Treatment with artesunate had a relatively mild side-effect profile; hypoglycemia was significantly more common with the use of quinine. A systematic review of five randomized trials comparing the efficacy of intravenous quinine with that of artesunate and one additional trial of intramuscular artesunate demonstrated the superiority of artesunate, with significant reductions in the risk of death (relative risk, 0.62), incidence of hypoglycemia, and parasite clearance time, as compared with quinine.32
Clinical Use
Of primary importance in the treatment of severe malaria are the provision of prompt, effective therapy and concurrent supportive care to manage life-threatening complications of the disease.2 In most of the world, standard therapy has been intravenous or intramuscular quinine. In the United States, intravenous quinidine has been the standard therapy since 1991. That year, parenteral quinine was withdrawn by the CDC because quinidine had been shown to be more potent in vitro and highly effective against P. falciparum when used orally for uncomplicated disease33 or intravenously for severe falciparum malaria.34 The current recommendations for severe malaria are to administer quinidine as a loading dose followed by continuous infusion; the loading dose may be omitted if quinine or mefloquine was recently administered.2,17 The cardiac toxic effects of quinidine are a major concern, and intravenous therapy requires continuous cardiac monitoring, with slowing or discontinuation of the infusion for prolongation of the QT interval. Another problem has been the decreasing availability of quinidine as the use of the drug as an antiarrhythmic agent has decreased.35
With emerging evidence of the superiority of artesunate over quinine or quinidine, an investigational-new-drug (IND) application from the CDC went into effect in the United States on June 21, 2007, to allow investigational use of intravenous artesunate for the treatment of severe malaria. The drug is not approved by the Food and Drug Administration, and it can be used in the United States only through the IND application, with the drug supplied at no charge by the Walter Reed Army Institute of Research. Patients are eligible if they have uncomplicated malaria but require parenteral therapy because of an inability to take oral medications or if they have a level of parasitemia of more than 5% or other signs of severe malaria (Table 1). In addition, the CDC requires that artesunate be at least as rapidly available for administration as quinidine or that there be known intolerance of quinidine, previous failure of such treatment, or a contraindication. Enrollment requires a telephone call to the CDC Malaria Hotline (Monday through Friday from 8 a.m. to 4:30 p.m. Eastern time, at 770-488-7788; at other times, health care providers may call 770-488-7100 and ask for a clinician in the CDC Malaria Branch). If approved, the drug will be released by the CDC Drug Service or by one of the 20 CDC quarantine stations located around the country.
Under the IND protocol, intravenous artesunate is administered in four equal doses of 2.4 mg per kilogram of body weight over a period of 3 days. The dosing schedule recommended by the World Health Organization (WHO) entails doses every 12 hours on day 1 and then once daily. Therapy for more than 3 days may occasionally be indicated in very ill patients, but specific guidelines on when to extend therapy are not available. Artesunate dosages need not be changed because of hepatic or renal failure or concomitant or previous therapy with other medications, including previous therapy with mefloquine, quinine, or quinidine. There are no known interactions between artesunate and other drugs.
Cardiac monitoring is not mandatory during treatment with artesunate, and no serious toxic effects due to the drug are anticipated. However, patients with severe malaria often require care in an intensive care unit. Indeed, aggressive supportive care, including mechanical ventilation and hemofiltration or hemodialysis, can be instrumental in successful management of severe malaria.36,37 In technologically limited settings, high-quality nursing care, management of fluid balance, and control of seizures are helpful, although anticonvulsant agents that are respiratory depressants should be used with caution if mechanical ventilation is unavailable.38 Aggressive fluid resuscitation, blood transfusion for moderate anemia, exchange transfusion, and specific treatment for acidosis are of uncertain value. Bacterial infections can coexist with severe malaria, so blood cultures should be obtained from patients with shock or other signs of sepsis despite appropriate antimalarial therapy, and these patients should receive broad-spectrum antibiotic therapy. Hypoglycemia will be less common when artesunate is used rather than quinine or quinidine; nonetheless, it is important to monitor the patient's blood glucose level and provide supplementary glucose as needed.
After the acute stage of the illness, artemisinins should be partnered with longer-acting drugs to ensure a high likelihood of cure. Appropriate partner drugs that are available in the United States are a 1-week course of doxycycline or, in children or pregnant women, clindamycin, or full courses of treatment with atovaquone–proguanil or mefloquine (although the neuropsychiatric toxic effects of mefloquine may be increased after cerebral malaria). All of these drugs should be initiated after the patient can tolerate oral medication.
Adverse Effects
Toxic effects have been reported less frequently with the artemisinins than with other antimalarial agents.39 The most common toxic effects that have been identified are nausea, vomiting, anorexia, and dizziness; these are probably due, in many patients, to acute malaria rather than to the drugs.40 More serious toxic effects, including neutropenia, anemia, hemolysis, and elevated levels of liver enzymes, have been noted rarely.41 Two cases of severe allergic reactions to oral artesunate have been reported, with an estimated risk of approximately 1 reaction per 3000 treatments.42
Neurotoxicity is the greatest concern regarding artemisinins, since the administration of high doses in laboratory animals has led to severe and irreversible changes in the brain.43 Extensive studies in many species showed that intramuscular dosing was more toxic than oral dosing and that, by any route, fat-soluble artemisinins were more toxic than artesunate.44 In humans, an episode of ataxia was reported after treatment with oral artesunate,45 and one case–control study showed hearing loss after the use of artemether–lumefantrine,46 but auditory toxic effects were not detected in another case–control study,47 and reported toxic effects may have been due to underlying malaria or other factors that were independent of artemisinin use. Multiple studies have shown that neurologic findings are fairly common with acute malaria, but there is no convincing evidence of neurotoxic effects resulting from standard oral or intravenous therapy with artemisinins.41,48,49
Another concern about artemisinins is embryotoxic effects, which have been demonstrated in animals.50 Studies from Asia51 and Africa,52 including 44 treatments during the first trimester,51 showed similar levels of congenital abnormalities, stillbirths, and abortions in patients who received and those who did not receive artesunate during pregnancy. Limited data are available on the use of intravenous artesunate for severe malaria during pregnancy.31
Areas of Uncertainty
A major concern with all antimalarial drugs is resistance. The short half-lives of artemisinins limit the possibility of selection for resistance. Nonetheless, recent heavy use of artemisinins, including monotherapy, has created selective pressure. Some parasites isolated from French Guiana and Senegal recently showed diminished in vitro sensitivity to artemether,53 and the efficacies of artemisinin-based combination agents have apparently decreased along the Thailand–Cambodia border.54 However, at present, the likelihood of true artemisinin resistance in malaria parasites is low, and this concern should not prevent the use of intravenous artesunate to treat severe malaria.
Guidelines
The WHO recommends intravenous artesunate as the treatment of choice for severe malaria in adults and children in areas of low transmission.13 Data on children in high-transmission regions are limited, and the WHO recommends treatment with artesunate, artemether, or quinine. For severe malaria during pregnancy, additional data regarding the risks of artemisinins are needed.55 The WHO recommends artesunate or quinine during the first trimester and artesunate as the first-line therapy during the second and third trimesters.
Recommendations
The patient in the vignette meets criteria for severe falciparum malaria (Table 1) and should receive emergency treatment in an intensive care unit, with careful attention to potential serious complications, since he is at high risk for rapid clinical deterioration. In particular, his respiratory findings and altered renal status require close observation, and mechanical ventilation and hemodialysis or hemofiltration may be required as his illness progresses. Until 2007, appropriate therapy would have been intravenous quinidine. Intravenous artesunate is now available. Since it has been shown to have superior efficacy and is likely to have fewer side effects and a better safety profile than intravenous quinidine, it is now appropriate therapy as long as it can be acquired promptly. This last point is a major concern, since intravenous artesunate will only be available rapidly for hospitals near CDC quarantine stations. If artesunate cannot be obtained promptly and quinidine is available, intravenous quinidine should be used. For either drug, a 3-day course should be given with either a 1-week course of doxycycline or a full course of treatment with atovaquone–proguanil or mefloquine.
Supported by grants from the National Institutes of Health and Medicines for Malaria Venture and a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation.
No potential conflicts of interest relevant to this article were reported.
I thank Dr. Nicholas J. White for a critical review of an earlier draft of this manuscript and helpful suggestions.
Source Information
From the Department of Medicine, San Francisco General Hospital, University of California, San Francisco.
Address reprint requests to Dr. Rosenthal at Box 0811, University of California, San Francisco, San Francisco, CA 94143, or at prosenthal@medsfgh.ucsf.edu .
References
1.Greenwood BM, Bojang K, Whitty CJ, Targett GA. Malaria. Lancet 2005;365:1487-1498. [CrossRef][ISI][Medline]
2.World Health Organization, Communicable diseases cluster: severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94:Suppl 1:S1-S90. (Also available at http://www.who.int/malaria/docs/hbsm_toc.htm.)
3.Hoffman SL, Campbell CC, White NJ. Malaria. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical infectious diseases: principles, pathogens, & practice. 2nd ed. Vol. 2. Philadelphia: Churchill Livingstone, 2006:1024-62.
4.Desai M, ter Kuile FO, Nosten F, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 2007;7:93-104. [CrossRef][ISI][Medline]
5.Chen LH, Wilson ME, Schlagenhauf P. Controversies and misconceptions in malaria chemoprophylaxis for travelers. JAMA 2007;297:2251-2263. [Free Full Text]
6.Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006;354:119-130. [Erratum, N Engl J Med 2006;355:967.] [Free Full Text]
7.Thwing J, Skarbinski J, Newman RD, et al. Malaria surveillance -- United States, 2005. MMWR Surveill Summ 2007;56:23-40. [Medline]
8.Ladhani S, Aibara RJ, Riordan FA, Shingadia D. Imported malaria in children: a review of clinical studies. Lancet Infect Dis 2007;7:349-357. [CrossRef][ISI][Medline]
9.Newman RD, Parise ME, Barber AM, Steketee RW. Malaria-related deaths among U.S. travelers, 1963-200Ann Intern Med 2004;141:547-55.
10.Flick K, Chen Q. var Genes, PfEMP1 and the human host. Mol Biochem Parasitol 2004;134:3-9. [CrossRef][ISI][Medline]
11.Mackintosh CL, Beeson JG, Marsh K. Clinical features and pathogenesis of severe malaria. Trends Parasitol 2004;20:597-603. [CrossRef][ISI][Medline]
12.Baird JK. Effectiveness of antimalarial drugs. N Engl J Med 2005;352:1565-1577. [Free Full Text]
13.Guidelines for the treatment of malaria. Geneva: World Health Organization, 2006. (Accessed March 28, 2008, at http://www.who.int/malaria/docs/TreatmentGuidelines2006.pdf.)
14.Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J 2005;81:71-78. [Free Full Text]
15.Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 2002;32:1655-1660. [CrossRef][ISI][Medline]
16.Eckstein-Ludwig U, Webb RJ, Van Goethem ID, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 2003;424:957-961. [CrossRef][Medline]
17.Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: a systematic review. JAMA 2007;297:2264-2277. [Free Full Text]
18.White NJ, Looareesuwan S, Warrell DA. Quinine and quinidine: a comparison of EKG effects during the treatment of malaria. J Cardiovasc Pharmacol 1983;5:173-175. [ISI][Medline]
19.Pukrittayakamee S, Supanaranond W, Looareesuwan S, Vanijanonta S, White NJ. Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand. Trans R Soc Trop Med Hyg 1994;88:324-327. [CrossRef][ISI][Medline]
20.Mutabingwa TK, Anthony D, Heller A, et al. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 2005;365:1474-1480. [CrossRef][ISI][Medline]
21.Smithuis F, Kyaw MK, Phe O, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet 2006;367:2075-2085. [CrossRef][ISI][Medline]
22.Karema C, Fanello CI, van Overmeir C, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg 2006;100:1105-1111. [CrossRef][ISI][Medline]
23.Dorsey G, Staedke S, Clark TD, et al. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA 2007;297:2210-2219. [Free Full Text]
24.Ratcliff A, Siswantoro H, Kenangalem E, et al. Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison. Lancet 2007;369:757-765. [CrossRef][ISI][Medline]
25.Zongo I, Dorsey G, Rouamba N, et al. Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Clin Infect Dis 2007;45:1453-1461. [CrossRef][ISI][Medline]
26.Karunajeewa HA, Manning L, Mueller I, Ilett KF, Davis TM. Rectal administration of artemisinin derivatives for the treatment of malaria. JAMA 2007;297:2381-2390. [Free Full Text]
27.van Hensbroek MB, Onyiorah E, Jaffar S, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996;335:69-75. [Free Full Text]
28.Hien TT, Day NPJ, Phu NH, et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996;335:76-83. [Free Full Text]
29.Artemether-Quinine Meta-analysis Study Group. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 2001;95:637-650. [CrossRef][ISI][Medline]
30.Hien TT, Davis TM, Chuong LV, et al. Comparative pharmacokinetics of intramuscular artesunate and artemether in patients with severe falciparum malaria. Antimicrob Agents Chemother 2004;48:4234-4239. [Erratum, Antimicrob Agents Chemother 2005;49:871.] [Free Full Text]
31.Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005;366:717-725. [CrossRef][ISI][Medline]
32.Jones KL, Donegan S, Lalloo DG. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2007;4:CD005967-CD005967. [Medline]
33.White NJ, Looareesuwan S, Warrell DA, Chongsuphajaisiddhi T, Bunnag D, Harinasuta T. Quinidine in falciparum malaria. Lancet 1981;2:1069-1071. [ISI][Medline]
34.Phillips RE, Warrell DA, White NJ, Looareesuwan S, Karbwang J. Intravenous quinidine for the treatment of severe falciparum malaria: clinical and pharmacokinetic studies. N Engl J Med 1985;312:1273-1278. [Abstract]
35.Rosenthal PJ, Petersen C, Geertsma FR, Kohl S. Availability of intravenous quinidine for falciparum malaria. N Engl J Med 1996;335:138-138. [Free Full Text]
36.Bruneel F, Hocqueloux L, Alberti C, et al. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 2003;167:684-689. [Free Full Text]
37.White NJ. The management of severe falciparum malaria. Am J Respir Crit Care Med 2003;167:673-674. [Free Full Text]
38.Day N, Dondorp AM. The management of patients with severe malaria. Am J Trop Med Hyg 2007;77:Suppl:29-35. [Free Full Text]
39.Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf 2004;27:25-61. [ISI][Medline]
40.Price R, van Vugt M, Phaipun L, et al. Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. Am J Trop Med Hyg 1999;60:547-555. [Abstract]
41.Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives: a review of published and unpublished clinical trials. Med Trop (Mars) 1998;58:Suppl:50-53. [Medline]
42.Leonardi E, Gilvary G, White NJ, Nosten F. Severe allergic reactions to oral artesunate: a report of two cases. Trans R Soc Trop Med Hyg 2001;95:182-183. [CrossRef][ISI][Medline]
43.Brewer TG, Grate SJ, Peggins JO, et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 1994;51:251-259. [Free Full Text]
44.Nontprasert A, Pukrittayakamee S, Nosten-Bertrand M, Vanijanonta S, White NJ. Studies of the neurotoxicity of oral artemisinin derivatives in mice. Am J Trop Med Hyg 2000;62:409-412. [Abstract]
45.Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997;336:1328-1328. [Free Full Text]
46.Toovey S, Jamieson A. Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether. Trans R Soc Trop Med Hyg 2004;98:261-269. [CrossRef][ISI][Medline]
47.Hutagalung R, Htoo H, Nwee P, et al. A case-control auditory evaluation of patients treated with artemether-lumefantrine. Am J Trop Med Hyg 2006;74:211-214. [Free Full Text]
48.Kissinger E, Hien TT, Hung NT, et al. Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients. Am J Trop Med Hyg 2000;63:48-55. [Abstract]
49.Van Vugt M, Angus BJ, Price RN, et al. A case-control auditory evaluation of patients treated with artemisinin derivatives for multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 2000;62:65-69. [Abstract]
50.Clark RL, White TE, A Clode S, Gaunt I, Winstanley P, Ward SA. Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit. Birth Defects Res B Dev Reprod Toxicol 2004;71:380-394. [CrossRef][ISI][Medline]
51.McGready R, Cho T, Keo NK, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis 2001;33:2009-2016. [CrossRef][ISI][Medline]
52.Deen JL, von Seidlein L, Pinder M, Walraven GE, Greenwood BM. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy. Trans R Soc Trop Med Hyg 2001;95:424-428. [CrossRef][ISI][Medline]
53.Jambou R, Legrand E, Niang M, et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 2005;366:1960-1963. [CrossRef][ISI][Medline]
54.Resistance to artemisinin derivatives along the Thai-Cambodian border. Wkly Epidemiol Rec 2007;82:360-360. [Medline]
55.Assessment of the safety of artemisinin compounds in pregnancy. Geneva: World Health Organization, 2007. (Accessed March 28, 2008, at http://malaria.who.int/docs/mip/artemisinin_compounds_pregnancy.pdf.)
Related Letters:
Artesunate for Malaria
Arguin P. M., Weina P. J., Dougherty C. P., Gordi T., Itskowitz M. S., Kashyap A. S., Anand K. P., Kashyap S., Rosenthal P. J.
Extract | Full Text | PDF
N Engl J Med 2008; 359:313-315, Jul 17, 2008. Correspondence
http://www.tm.mahidol.ac.th/seameo/2008/39_4/06-4249.pdf
A COMPARISON OF DENGUE HEMORRHAGIC FEVER
CONTROL INTERVENTIONS IN NORTHEASTERN
THAILAND
Anun Chaikoolvatana1, Suparat Chanruang1 and Prakongsil Pothaled2
1Department of Pharmaceutical Sciences, Ubon Rajathanee University; 2Health Care
Management Master Program, Ubon Rajathanee University, Ubon Ratchathani, Thailand
Abstract. This study compared the effectiveness of the currently available interventions of dengue
vector and dengue hemorrhagic fever (DHF) control used in northeastern Thailand, an
area with a high incidence of the disease. Also, the basic knowledge of dengue vector and
DHF control of a group of 568 participants from local communities was measured. These
communities were divided into two groups that had no reported cases in the previous year
(non-DHF) and a group that had reported cases (DHF). Three current interventions of dengue
vector and DHF control were assessed: insecticide fogging, 1% w/w temephos sand granules,
and a combination of these two. Assessment included numbers of DHF cases, vector indices
[house index (HI), container index (CI), and Breteau index (BI)], and cost. A multiple choice
questionnaire was used to measure participants' basic knowledge desirable for knowledge
retention. Data was statistically analyzed by the use of means, standard deviations, percentages,
ANOVA repeated measure, and logistic regression. The results showed 1% w/w temephos
sand granules as the most effective intervention of dengue vector and DHF control and there
was a statistically significant difference between the control measures (p =0.001). Most participants
had either a very low or very high level of knowledge and basic knowledge was statistically
significantly associated with vector index (BI) (p = 0.008). Participants stated that they
mainly gained knowledge about dengue vector and DHF control from public health workers
followed by television and public media. Overall, the findings of this study illustrated the importance
of public health workers and communities in health issues at the local level and the need
to assess the benefits of current interventions and combinations of current and new interventions of dengue vector and control.
Correspondence: Asst Prof Anun Chaikoolvatana,
Pharmacy Practice Group, Department of Pharmaceutical
Sciences, Ubon Rajathanee University,
Ubon Ratchathani, Thailand.
Tel: 66 (045) 353671; Fax: 66 (045) 288384
E-mail: kkjc5476@yahoo.com, phanunch@hotmail.
Com
http://content.nejm.org/cgi/content/full/349/16/1510
Delayed Onset of Malaria — Implications for Chemoprophylaxis in Travelers
Eli Schwartz, M.D., Monica Parise, M.D., Phyllis Kozarsky, M.D., and Martin Cetron, M.D.
ABSTRACT
Background Most antimalarial agents used by travelers act on the parasite's blood stage and therefore do not prevent late-onset illness, particularly that due to species that cause relapsing malaria. We examined the magnitude of this problem among Israeli and American travelers.
Methods We examined malaria surveillance data from Israel and the United States to determine the traveler's destination, the infecting species, the type of chemoprophylaxis used, and the incubation period.
Results In Israel, from 1994 through 1999, there were 300 cases of malaria among returning travelers in which one species of plasmodium could be identified. In 134 of these cases (44.7 percent), the illness developed more than two months after the traveler's return; nearly all of these cases were due to infection with Plasmodium vivax or P. ovale. In 108 of the 134 cases (80.6 percent), the patient had used an antimalarial regimen according to national guidelines. In the United States, from 1992 through 1998, there were 2822 cases of malaria among travelers in which the cause could be evaluated. Late illness developed in 987 (35.0 percent) of these travelers. The infection was due to P. vivax in 811 travelers, P. ovale in 66, P. falciparum in 59, and P. malariae in 51; 614 (62.2 percent) of those with late-onset illness had appropriately taken an effective antimalarial agent.
Conclusions In more than one third of malaria-infected travelers, the illness developed more than two months after their return. Most of these late-onset illnesses are not prevented by the commonly used and effective blood schizonticides. Agents that act on the liver phase of malaria parasites are needed for more effective prevention of malaria in travelers.
The appropriate choice of drugs for chemoprophylaxis against malaria in travelers remains controversial and is affected by several issues, including drug efficacy, tolerance, convenience, and cost. The declining efficacy of chloroquine against Plasmodium falciparum in most malarious areas of the world precludes the routine use of this drug, which was the mainstay of prophylaxis and treatment for decades. Given the low risk of infection for many travelers, drug tolerance may limit use if adverse effects are too frequent or severe. For example, amodiaquine and sulfadoxine–pyrimethamine were found to have low but unacceptable rates of severe adverse effects.1,2,3 Concern about adverse effects of mefloquine (particularly those related to the central nervous system)4,5 has led to decreased use and compliance.6 Doxycycline has good efficacy against both P. falciparum and P. vivax,7,8 but adherence may be limited by gastrointestinal side effects.9 In addition, there may be lower adherence to treatment with agents that need to be taken daily rather than weekly,10 which reduces their effectiveness.11,12
An important factor in weighing the advantages and disadvantages of the various chemoprophylactic agents that are available is their site of action in the life cycle of the parasite. Most of the available chemoprophylactic agents are blood-stage schizonticides that do not affect the liver stage of the parasite and therefore will not prevent the late appearance of species that cause relapsing malaria. These late-onset illnesses due to P. vivax and P. ovale can become clinically apparent in travelers months after their return from areas of endemic malaria despite adherence to nationally recommended chemoprophylactic regimens. We examined the magnitude of the problem among Israeli and American travelers.
Methods
Malaria is a notifiable disease in both Israel and the United States; malaria surveillance is conducted by the Epidemiology Department of the Ministry of Health in Israel and by the Malaria Epidemiology Branch of the Division of Parasitic Diseases at the Centers for Disease Control and Prevention (CDC) in the United States. In both countries, cases are defined by parasitemia confirmed by blood smear. In Israel, a nurse-epidemiologist interviews each patient with malaria and records the purpose of the travel, the travel itinerary, and the use or nonuse of chemoprophylaxis against malaria. In the United States, similar data are sent from local and state health departments to the CDC. We analyzed surveillance data from Israel and the United States for the periods from 1994 through 1999 and from 1992 through 1998, respectively. Only civilian residents of these countries were included in the analyses.
Results
During the years 1994 through 1999, there were 307 reported cases of malaria among returning Israeli travelers. The most frequently reported species was P. vivax, with 156 cases (50.8 percent), followed by P. falciparum, with 135 cases (44.0 percent), P. ovale, with 5 cases (1.6 percent), and P. malariae, with 4 cases (1.3 percent). In seven cases (2.3 percent), the species was undetermined (six cases) or the illness was due to a mixed infection (one case); these were excluded from the analysis.
All cases of P. falciparum malaria in Israel were detected within two months after the traveler's return (Table 1). Ninety-seven of the 135 persons who acquired P. falciparum infection (71.9 percent) had not used any chemoprophylaxis. Twenty-four (17.8 percent) admitted noncompliance or had used chloroquine alone or the combination of chloroquine and chloroguanide in areas with chloroquine-resistant P. falciparum; only 14 (10.4 percent) had used effective agents (e.g., mefloquine or doxycycline) for travel to areas with chloroquine-resistant P. falciparum.
View this table:
[in this window]
[in a new window]
Table 1. Characteristics of Imported Cases of Malaria among 300 Israeli Travelers from 1994 through 1999.
In contrast, in 133 of 161 persons with P. vivax or P. ovale malaria (82.6 percent), the onset of illness occurred more than two months after the traveler's return. One hundred eight (81.2 percent) of these travelers had used what was presumed to be an effective prophylactic regimen; 70 percent had taken mefloquine. These 108 cases represent 36 percent of the 300 cases of malaria whose cause could be attributed to a single species.
In the United States, from 1992 through 1998, epidemiologic information was available for 2964 of 5185 reported cases of malaria. P. vivax and P. falciparum accounted for 1321 (44.6 percent) and 1290 (43.5 percent) of these cases, respectively; 124 (4.2 percent) were due to P. malariae, 87 (2.9 percent) were due to P. ovale, and 2 (0.07 percent) were mixed infections. The species was undetermined in 140 cases (4.7 percent). After mixed infections and infections by undetermined species had been excluded, 2822 cases remained for analysis (Table 2).
View this table:
[in this window]
[in a new window]
Table 2. Characteristics of Imported Cases of Malaria among 2822 U.S. Travelers from 1992 through 1998.
More than 95 percent of patients with P. falciparum malaria presented within two months after their return. Eight hundred sixty-three of 1231 patients (70.1 percent) had used no chemoprophylaxis, and 201 (16.3 percent) had taken a drug that was not considered effective for the prevention of malaria in the area to which they traveled (most commonly chloroquine in areas of chloroquine-resistant P. falciparum). Only 167 patients (13.6 percent) had taken an agent that was effective for the prevention of malaria in the area to which they traveled. Among those who took an effective drug but still acquired P. falciparum malaria, mefloquine was used most frequently (by 73.3 percent of the patients). Information was not available on adherence to the chemoprophylactic regimen, nor were samples available for determination of the blood levels of the antimalarial drugs; therefore, possible mefloquine resistance could not be properly evaluated in these patients.
In contrast, in 877 of the 1408 persons who acquired P. vivax or P. ovale malaria (62.3 percent), the onset of symptoms occurred more than two months after their return. The median time from exposure (with the end of the trip arbitrarily chosen as the time of exposure) to the onset of symptoms among those with late-onset illness was 181 days (range, 61 to 1712). Of these 877 patients, 322 (36.7 percent) had used no chemoprophylaxis, whereas 555 (63.3 percent) had taken an antimalarial regimen that should have eliminated the blood stages of P. vivax or P. ovale. Mefloquine was the most commonly used drug, taken by 293 patients (52.8 percent), followed by chloroquine, which was taken by 184 patients (33.2 percent). In 555 of the 2822 U.S. cases (19.7 percent), late illness due to P. vivax or P. ovale developed despite the use of an effective antimalarial regimen.
Discussion
A 50 percent infection rate with P. vivax among Israeli travelers (who had adhered to mefloquine prophylaxis) three months after their return from Ethiopia called attention to the gap in coverage with currently available drugs.13 This led to the current review of this problem in Israel and the United States. We found that up to one third of all reported cases of malaria in both Israel and the United States were late-onset illnesses caused by P. vivax or P. ovale that occurred despite adequate blood-stage prophylaxis.
Although malaria typically occurs in travelers because of lack of pretravel health information, poor compliance resulting in inadequate drug levels, or drug resistance, these factors do not appear to account for the late onset of illness in the patients in this study. In fact, the acquisition of malaria by travelers despite their adherence to medical recommendations may result in reduced compliance and decreased trust in the advice given by health care providers. Moreover, the diagnosis of late-onset illness in travelers who have used a nationally recommended antimalarial regimen is more challenging for physicians and may be more difficult for patients to associate with previous travel. The phenomenon of late-onset illness is not well understood, and many physicians and travelers believe that the use of prophylaxis against malaria should prevent all cases of infection.
The life cycle of the parasite in humans consists of two stages. In the initial stage, known as the liver or exoerythrocytic stage, the parasites multiply in the hepatocytes and eventually cause them to rupture. Two species, P. vivax and P. ovale, have persistent liver stages, which can emerge and cause a relapse months to years later. The use of blood-stage schizonticides will not prevent these relapses. In addition, their use can mask symptoms of the first infection with P. vivax or P. ovale. The first apparent symptoms of infection may then occur months later.
The second stage, the blood or erythrocytic stage, occurs when the parasites are released into the bloodstream, invade the erythrocytes, and cause clinical illness. We defined an early-onset illness as one in which the first clinical presentation was within two months after exposure to the parasite (taking into account the fact that patients may have followed a chemoprophylactic regimen for up to four weeks after travel); such infections may be due to any of the malaria species. An early-onset illness is usually prevented if a traveler adheres to one of the nationally recommended antimalarial chemoprophylactic regimens just before, during, and after travel.
The current model for chemoprophylaxis divides the areas of the world in which malaria is endemic into two zones: one with chloroquine-sensitive P. falciparum and one with chloroquine-resistant P. falciparum. The resistance of P. falciparum to chloroquine has been confirmed in all areas with P. falciparum malaria except the Dominican Republic, Haiti, Central America west of the former Panama Canal Zone, Egypt, and some countries in the Middle East.14,15 Although this model has been serviceable for decades for the primary purpose of preventing lethal malaria due to P. falciparum, it clearly ignores a substantial portion of the burden of malaria acquired through travel — infections due to P. vivax (and, to a much lesser extent, P. ovale).
The current strategy for prevention of P. vivax and P. ovale relapses includes the addition of two weeks of terminal prophylaxis with primaquine for travelers who have had prolonged exposure to areas where those species are endemic.14 Unfortunately, this approach has a number of inherent problems. The recommendations are confusing and are not well communicated to health care providers. The geographic distribution of the areas where travelers are exposed to the species causing relapsing malaria is not defined in national guidelines for chemoprophylaxis, and the requirement of two antimalarial medications increases the likelihood of adverse events, increases the cost, and decreases compliance (which is often lower after a return from travel).16,17
The types of chemoprophylaxis against malaria are summarized in Table 3. Liver-stage (causal) prophylaxis, by acting on the hepatic phase, theoretically offers the most complete protection, since it may actually prevent primary infections by all malaria species, as well as late relapses. Liver-stage prophylaxis (provided that an effective agent was taken and the regimen was adhered to) might have prevented infection in the persons in our study who had late-onset illness from P. falciparum or P. malariae. Liver-stage prophylaxis should also enable travelers to discontinue prophylaxis at the time of or soon after departure from malarious areas, thus increasing adherence. In areas where there is transmission of only P. vivax or of P. vivax and other species (Figure 1), liver-stage prophylaxis offers definite advantages. In areas where P. falciparum is overwhelmingly dominant, protection is similar with liver- and blood-stage prophylaxis (although liver-stage prophylaxis still offers the advantage that it can be discontinued when the traveler leaves the malarious area).
View this table:
[in this window]
[in a new window]
Table 3. Types of Chemoprophylaxis against Malaria.
View larger version (28K):
[in this window]
[in a new window]
Figure 1. Species-Specific Areas Where Malaria Is Endemic.
In sub-Saharan Africa, where P. falciparum accounts for more than 90 percent of infections in most areas, blood-stage prophylaxis is sufficient. However, in the Horn of Africa (Ethiopia and Somalia), a large proportion of infections are caused by P. vivax, and thus prophylaxis against blood-stage parasites alone would lead to gaps in coverage. In most malarious areas outside sub-Saharan Africa, where both P. falciparum and P. vivax are transmitted, liver-stage prophylaxis would also provide the most complete protection.
Unfortunately, the number of available agents for liver-stage prophylaxis and our experience with these agents are limited. The agents are primaquine and atovaquone–chloroguanide (Malarone).18,19,20 Although primaquine has been used primarily for terminal prophylaxis (presumptive eradication of hypnozoites) or radical cure of relapsing malaria, it has been evaluated as a chemoprophylactic agent and has been effective in several studies, with protective efficacy of more than 90 percent for P. falciparum malaria and from 85 to 90 percent for P. vivax malaria.21,22,23 It has been well tolerated, even during long-term use.21 To date, the only study that has evaluated the prophylactic efficacy of primaquine among travelers without immunity to malaria involved Israeli tourists taking rafting trips in areas of Ethiopia where malaria is highly endemic.24 In this study, the overall rate of malaria infection during a two-week trip was 52 percent among travelers who took mefloquine (13 of 25 persons became infected), as compared with 6 percent among those who took primaquine (6 of 106 persons). During a mean follow-up of 16 months, there were no cases of late-onset illness among the primaquine users. The main disadvantage of primaquine is the risk of hemolysis in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The time required to test the blood for G6PD deficiency before using primaquine and the cost of the test remain problems.
The combination of atovaquone and chloroguanide has blood-stage and liver-stage activity.19,20,25 The combination has proved effective for the treatment of P. falciparum malaria,26,27,28,29,30,31,32,33,34 has been shown to be effective for chemoprophylaxis against P. falciparum malaria in both semi-immune35,36,37 and nonimmune persons,38 and has been well tolerated by nonimmune persons.39,40 However, data on the efficacy of the combination for the treatment of and prophylaxis against P. vivax malaria are more limited.27,38,41
Tafenoquine, an 8-aminoquinolone thought to provide complete prophylaxis, is undergoing clinical trials. A major advantage of tafenoquine is its long elimination half-life of 14 days,42 which would allow for either weekly dosing or possibly a short course of medication before a trip lasting less than 1 or 2 months. Studies in Kenya and Gabon have shown that tafenoquine has excellent prophylactic efficacy against P. falciparum.43
The development of new agents for the prevention of malaria that act against the liver stage could provide attractive chemoprophylactic alternatives. In addition to efficacy, factors that should be weighed in considering the appropriateness of chemoprophylaxis against malaria include tolerability, pharmacokinetic properties that determine dosing frequency, and cost.
Dr. Kozarsky reports having received consulting fees from GlaxoSmithKline.
The use of trade names is for identification only and does not imply endorsement by the Public Health Service or the Department of Health and Human Services.
We are indebted to Jacquelin Roberts for statistical support at the CDC and to Dr. P. Slater and his staff in the Department of Epidemiology, Ministry of Health, Jerusalem, Israel, for providing Israeli malaria surveillance data.
Source Information
From the Center for Geographical Medicine and the Department of Medicine, C. Chaim Sheba Medical Center, Tel Hashomer, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (E.S.); and the Malaria Epidemiology Branch, Division of Parasitic Diseases (M.P.), and the Surveillance and Epidemiology Branch, Division of Global Migration and Quarantine (M.C.), National Center for Infectious Diseases, Centers for Disease Control and Prevention; the Public Health Service, Department of Health and Human Services (M.P., M.C.); and the Department of Medicine, Emory University School of Medicine (P.K.) — all in Atlanta.
Address reprint requests to Dr. Schwartz at the Center for Geographical Medicine and the Department of Medicine, C. Chaim Sheba Medical Center, Tel Hashomer 52621, Israel, or at elischwa@post.tau.ac.il .
References
1.Hatton CS, Peto TE, Bunch C, et al. Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet 1986;1:411-414. [CrossRef][Medline]
2.Neftel KA, Woodtly W, Schmid M, Frick PG, Fehr J. Amodiaquine induced agranulocytosis and liver damage. Br Med J (Clin Res Ed) 1986;292:721-723.
3.Miller KD, Lobel HO, Satriale RF, Kuritsky JN, Stern R, Campbell CC. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986;35:451-458. [Free Full Text]
4.Hennequin C, Bouree P, Bazin N, Bisaro F, Feline A. Severe psychiatric side effects observed during prophylaxis and treatment with mefloquine. Arch Intern Med 1994;154:2360-2362. [Abstract]
5.Croft AM, World MJ. Neuropsychiatric reactions with mefloquine chemoprophylaxis. Lancet 1996;347:326-326. [CrossRef][ISI][Medline]
6.Croft A, Garner P. Mefloquine to prevent malaria: a systematic review of trials. BMJ 1997;315:1412-1416. [Free Full Text]
7.Ohrt C, Richie TL, Widjaja H, et al. Mefloquine compared with doxycycline for the prophylaxis of malaria in Indonesian soldiers: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997;126:963-972. [Free Full Text]
8.Taylor WR, Richie TL, Fryauff DJ, et al. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis 1999;28:74-81. [ISI][Medline]
9.Baudon D, Martet G, Pascal B, Bernard J, Keundjian A, Laroche R. Efficacy of daily antimalarial chemoprophylaxis in tropical Africa using either doxycycline or chloroquine-proguanil: a study conducted in 1996 in the French Army. Trans R Soc Trop Med Hyg 1999;93:302-303. [CrossRef][ISI][Medline]
10.Steffen R, Heusser R, Machler R, et al. Malaria chemoprophylaxis among European tourists in tropical Africa: use, adverse reactions, and efficacy. Bull World Health Organ 1990;68:313-322. [ISI][Medline]
11.Sanchez JL, DeFraites RF, Sharp TW, Hanson RK. Mefloquine or doxycycline prophylaxis in US troops in Somalia. Lancet 1993;341:1021-1022. [Medline]
12.Wallace MR, Sharp TW, Smoak B, et al. Malaria among United States troops in Somalia. Am J Med 1996;100:49-55. [CrossRef][ISI][Medline]
13.Schwartz E, Sidi Y. New aspects of malaria imported from Ethiopia. Clin Infect Dis 1998;26:1089-1091. [ISI][Medline]
14.Centers for Disease Control and Prevention. Health information for the international traveler 2001-2002. Atlanta: Public Health Service, 2001.
15.International travel and health: vaccination requirements and health advice: situation as on 1 January 2000. Geneva: World Health Organization, 2000.
16.Phillips-Howard PA, Blaze M, Hurn M, Bradley DJ. Malaria prophylaxis: survey of the response of British travellers to prophylactic advice. Br Med J (Clin Res Ed) 1986;293:932-934.
17.Lobel HO, Phillips-Howard PA, Brandling-Bennett AD, et al. Malaria incidence and prevention among European and North American travellers to Kenya. Bull World Health Organ 1990;68:209-215. [ISI][Medline]
18.Alving AS. Status of primaquine. 1. Mass therapy of subclinical vivax malaria with primaquine. JAMA 1952;149:1558-1562.
19.Berman JD, Nielsen R, Chulay JD, et al. Causal prophylactic efficacy of atovaquone-proguanil (Malarone) in a human challenge model. Trans R Soc Trop Med Hyg 2001;95:429-432. [CrossRef][ISI][Medline]
20.Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P. Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg 1999;60:831-836. [Abstract]
21.Fryauff DJ, Baird JK, Basri H, et al. Randomised placebo-controlled trial of primaquine for prophylaxis of falciparum and vivax malaria. Lancet 1995;346:1190-1193. [CrossRef][ISI][Medline]
22.Soto J, Toledo J, Rodriquez M, et al. Primaquine prophylaxis against malaria in nonimmune Colombian soldiers: efficacy and toxicity: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129:241-244. [Free Full Text]
23.Baird JK, Lacy MD, Basri H, et al. Randomized, parallel placebo-controlled trial of primaquine for malaria prophylaxis in Papua, Indonesia. Clin Infect Dis 2001;33:1990-1997. [CrossRef][ISI][Medline]
24.Schwartz E, Regev-Yochay G. Primaquine as prophylaxis for malaria for nonimmune travelers: a comparison with mefloquine and doxycycline. Clin Infect Dis 1999;29:1502-1506. [CrossRef][ISI][Medline]
25.Shanks GD, Kremsner PG, Sukwa TY, et al. Atovaquone and proguanil hydrochloride for prophylaxis of malaria. J Travel Med 1999;6:Suppl 1:S21-S27.
26.de Alencar FE, Cerutti C Jr, Durlacher RR, et al. Atovaquone and proguanil for the treatment of malaria in Brazil. J Infect Dis 1997;175:1544-1547. [ISI][Medline]
27.Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 1996;54:62-66. [Free Full Text]
28.Looareesuwan S, Wilairatana P, Chalermarut K, Rattanapong Y, Canfield CJ, Hutchinson DB. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 1999;60:526-532. [Abstract]
29.Bustos DG, Canfield CJ, Canete-Miguel E, Hutchinson DB. Atovaquone-proguanil compared with chloroquine and chloroquine-sulfadoxine-pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. J Infect Dis 1999;179:1587-1590. [CrossRef][ISI][Medline]
30.Mulenga M, Sukwa TY, Canfield CJ, Hutchinson DB. Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia. Clin Ther 1999;21:841-852. [CrossRef][ISI][Medline]
31.Radloff PD, Philipps J, Nkeyi M, Hutchinson D, Kremsner PG. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 1996;347:1511-1514. [CrossRef][ISI][Medline]
32.Sabchareon A, Attanath P, Phanuaksook P, et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1998;92:201-206. [CrossRef][ISI][Medline]
33.Anabwani G, Canfield CJ, Hutchinson DB. Combination atovaquone and proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children. Pediatr Infect Dis J 1999;18:456-461. [CrossRef][ISI][Medline]
34.Lacy MD, Maguire JD, Barcus MJ, et al. Atovaquone/proguanil therapy for Plasmodium falciparum and Plasmodium vivax malaria in Indonesians who lack clinical immunity. Clin Infect Dis 2002;35:e92-e95. [CrossRef][ISI][Medline]
35.Shanks GD, Gordon DM, Klotz FW, et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis 1998;27:494-499. [ISI][Medline]
36.Sukwa TY, Mulenga M, Chisdaka N, Roskell NS, Scott TR. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg 1999;60:521-525. [Abstract]
37.Lell B, Luckner D, Ndjave M, Scott T, Kremsner PG. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998;351:709-713. [CrossRef][ISI][Medline]
38.Ling J, Baird JK, Fryauff DJ, et al. Randomized, placebo-controlled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin Infect Dis 2002;35:825-833. [CrossRef][ISI][Medline]
39.Hogh B, Clarke PD, Camus D, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travelers: a randomised, double-blind study. Lancet 2000;356:1888-1894. [CrossRef][ISI][Medline]
40.Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001;33:1015-1021. [CrossRef][ISI][Medline]
41.Looareesuwan S, Wilairatana P, Glanarongran R, et al. Atovaquone and proguanil hydrochloride followed by primaquine for treatment of Plasmodium vivax malaria in Thailand. Trans R Soc Trop Med Hyg 1999;93:637-640. [CrossRef][ISI][Medline]
42.Brueckner RP, Lasseter KC, Lin ET, Schuster BG. First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial. Am J Trop Med Hyg 1998;58:645-649. [Abstract]
43.Lell B, Faucher JF, Missinou MA, et al. Malaria chemoprophylaxis with tafenoquine: a randomised study. Lancet 2000;355:2041-2045. [CrossRef][Medline]
http://bankdata.depkes.go.id/Profil/INDEX.HTM
PERSENTASE 10 PENYAKIT UTAMA PADA PASIEN RAWAT JALAN
DI RUMAH SAKIT DI INDONESIA TAHUN 2003
No.
DTD
Golongan Sebab Sakit
%
(1)
(2)
(3)
(4)
1
167
Infeksi Saluran Nafas Bagian Atas
8.5
2
007.0-1
Tuberkulosis Paru
3.7
3
104.0-9
Diabetes Militus
3.4
4
199
Penyakit Kulit dan Jaringan Subkutan Lainnya
2.9
5
5
Diare dan Gastroenteritis Infeksi tertentu (Colitis Infeksi)
2.7
6
281
Cedera YDT Lainnya, YTT dan Daerah Badan Multipel
2.4
7
145
Hipertensi Esensial (Primer)
2.3
8
184
Gastritis Duodentis
1.7
9
181.2
Penyakit Pulpa dan Periaptikal
1.6
10
185.0
Dispepsia
1.5
Sumber: Ditjen Yanmed Depkes RI, 2003
Keterangan: DTD (Daftar Tabulasi Dasar)
Lampiran 3.3
PERSENTASE 10 PENYAKIT UTAMA PADA PASIEN RAWAT INAP
DI RUMAH SAKIT DI INDONESIA TAHUN 2003
No.
DTD
Golongan Sebab Sakit
%
(1)
(2)
(3)
(4)
1
005
Diare dan Gastroenteritis Infeksi tertentu (Colitis Infeksi)
8.0
2
032.1
Demam Berdarah Dengue
3.7
3
242.9
Penyakit Kehamilan dan Persalinan Lainnya
2.9
4
002
Demam Tifoid dan Paratifoid
2.7
5
278
Cedera Intrakranial
2.0
6
007.0-1
Tuberkulosis Paru
1.9
7
268
Demam yang sebabnya tidak diketahui
1.9
8
104.0-9
Diabetes Militus
1.9
9
281
Cedera YDT Lainnya, YTT dan Daerah Badan Multipel
1.8
10
169
Pneumonia
1.6
Sumber: Ditjen Yanmed Depkes RI, 2003
Keterangan: DTD (Daftar Tabulasi Dasar)
JUMLAH KASUS DAN ANGKA KESAKITAN PENYAKIT MALARIA
MENURUT PROVINSI TAHUN 2003
No.
Provinsi
Jumlah Penderita
API/AMI
(1)
(2)
(3)
(4)
????? 1
?Nanggroe Aceh Darussalam
20,440
4.94
????? 2
?Sumatera Utara
64,419
7.23
????? 3
?Sumatera Barat
8,651
2.21
????? 4
?Riau
28,495
6.06
????? 5
?Jambi
60,127
24.4
????? 6
?Sumatera Selatan
52,263
7.4
????? 7
?Bengkulu
40,476
25.63
????? 8
?Lampung
62,634
8.39
????? 9
?Kepulauan Bangka Belitung
37,014
39.88
??? 10
?DKI Jakarta
-
-
??? 11
?Jawa Barat
60,024
0.16
??? 12
?Jawa Tengah
351,905
0.51
??? 13
?DI Yogyakarta
81,984
0.97
??? 14
?Jawa Timur
233,108
0.08
??? 15
?Banten
-
-
??? 16
?Bali
23,444
0.03
??? 17
?Nusa Tenggara Barat
97,643
25.17
??? 18
?Nusa Tenggara Timur
633,462
177.61
??? 19
?Kalimantan Barat
104,019
26.26
??? 20
?Kalimantan Tengah
6,178
7.78
??? 21
?Kalimantan Selatan
18,315
5.35
??? 22
?Kalimantan Timur
19,428
3.83
??? 23
?Sulawesi Utara
44,777
21.01
??? 24
?Sulawesi Tengah
44,078
21.63
??? 25
?Sulawesi Selatan
18,315
2.40
??? 26
?Sulawesi Tenggara
38,480
21.11
??? 27
?Gorontalo
16,202
19.04
??? 28
?Maluku
62,295
45.92
??? 29
?Maluku Utara
72,231
80.03
??? 30
?Papua
185,428
72.60
Indonesia
2,485,835
63.56
Sumber: Ditjen PPM-PL Depkes RI
Keterangan: (-) tidak ada data
??????????????????? API = Annual Parasite Incidence (di P. Jawa + Bali)
??????????????????? AMI = Annual Malaria Incidence (di luar P. Jawa + Bali)
ANNUAL PARASITE INCIDENCE (API) MALARIA
DI JAWA-BALI TAHUN 1997 -? 2003
No.
Provinsi
Annual Parasite Incidence (API) Per 1.000
1997
1998
1999
2000
2001
2002
2003
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
1
?DKI Jakarta
0.000
0.000
0.000
0.070
0.010
0.01
-
2
?Jawa Barat
0.040
0.070
0.040
0.030
0.020
0.02
0.23
3
?Jawa Tengah
0.320
0.650
1.060
1.740
1.460
1.44
0.15
4
?DI Yogyakarta
0.520
3.540
6.760
11.730
10.430
8.17
-
5
?Jawa Timur
0.040
0.030
0.050
0.170
0.120
0.07
0.08
6
?Banten
-
-
-
-
-
16
-
7
?Bali
0.030
0.030
0.040
0.040
0.080
0.06
0.04
Jawa-Bali
0.120
0.300
0.520
0.810
0.620
16.06
0.04
Sumber : Ditjen PPM-PL Depkes RI
Keterangan: (-) tidak ada data
JUMLAH KASUS DAN ANGKA INSIDENS PENYAKIT CAMPAK, DIFTERI, PERTUSIS DAN HEPATITIS PER 10.000 PENDUDUK
MENURUT KELOMPOK UMUR DAN PROVINSI TAHUN 2003
No.
Provinsi
Campak
Difteri
Pertusis
Hepatitis
Umur <1
Umur 1-4
Umur 5-14
Jumlah Umur??? 0-14
Umur <1
Umur 1-4
Umur 5-14
Jumlah Umur??? 0-14
Umur <1
Umur 1-4
Umur 5-14
Jumlah Umur??? 0-14
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
?? 1
?Nanggroe Aceh D.
269
25.2
759
28.5
685
8.12
1,713
12
1.13
9
0.34
2
0.02
23
212
19.88
208
7.82
85
1.01
505
541
1.30
?? 2
?Sumatera Utara
315
10.5
768
8
966
3.78
2,049
1
0.03
3
0.03
7
0.03
11
150
4.99
513
5.37
312
1.22
975
1,636
1.30
?? 3
?Sumatera Barat
0
0.00
0
0.00
0
0.00
0
0
0.00
0
0.00
0
0.00
0
0
0.00
0
0.00
0
0.00
0
80
0.20
?? 4
?Riau
119
8.7
345
7.0
419
3.74
883
2
0.15
5
0.10
6
0.05
13
7
0.51
10
0.20
7
0.06
24
177
0.30
?? 5
?Jambi
79
12.6
140
6.7
158
2.82
377
0
0.00
2
0.10
0
0.00
2
13
2.08
29
1.39
20
0.36
62
125
0.50
?? 6
?Sumatera Selatan
143
8.4
407
6.6
362
2.25
912
0
0.00
4
0.07
2
0.01
6
4
0.24
12
0.20
17
0.11
33
746
1.00
?? 7
?Bengkulu
22
5.5
50
3.7
91
2.59
163
0
0.00
0
0.0
0
0.00
0
0
0.00
0
0.00
1
0.03
1
53
0.30
?? 8
?Lampung
65
3.9
113
2.0
152
0.99
330
7
0.42
7
0.13
9
0.06
23
0
0.00
60
1.08
216
1.41
276
14,491
20.60
?? 9
?Kep. Bangka Belitung
5
2.1
21
1.7
13
0.69
39
0
0.00
0
0.00
0
0.00
0
2
0.83
3
0.24
8
0.43
13
29
0.30
?10
?DKI Jakarta
281
14.0
474
9.2
414
2.65
1,169
0
0.00
3
0.06
2
0.01
5
12
0.60
13
0.25
4
0.03
29
1,004
1.20
?11
?Jawa Barat
663
7.5
1,614
5.9
1,471
2.04
3,748
3
0.03
2
0.01
3
0.00
8
17
0.19
66
0.24
61
0.08
144
2,690
0.70
?12
?Jawa Tengah
7
0.1
33
0.1
18
0.03
58
0
0.00
3
0.01
11
0.02
14
1
0.02
1
0.00
1
0.00
3
283
0.10
?13
?DI Yogyakarta
26
5.1
156
11.1
322
7.17
504
0
0.00
0
0.00
0
0.00
0
1
0.19
0
0.00
0
0.00
1
193
0.60
?14
?Jawa Timur
245
3.9
815
4.2
1,102
1.89
2,162
1
0.02
14
0.07
17
0.03
32
27
0.43
55
0.29
29
0.05
111
2,135
0.60
?15
?Banten
358
16.4
1,006
13.7
828
4.39
2,192
1
0.05
5
0.07
1
0.01
7
15
0.69
55
0.75
48
0.25
118
1,341
1.60
?16
?Bali
38
6.2
115
5.4
203
3.85
356
0
0.00
0
0.00
0
0.00
0
7
1.15
17
0.80
14
0.27
38
317
1.00
?17
?Nusa Tenggara Barat
30
2.9
159
4.4
121
1.27
310
0
0.00
0
0.00
0
0.00
0
0
0.00
0
0.00
0
0.00
0
132
0.30
?18
?Nusa Tenggara Timur
14
1.3
25
0.7
31
0.32
70
0
0.00
4
0.12
12
0.12
16
7
0.63
16
0.47
11
0.11
34
215
0.50
?19
?Kalimantan Barat
166
18.1
267
7.2
277
2.86
710
0
0.00
0
0.00
0
0.00
0
54
5.88
104
2.80
36
0.37
194
889
2.10
?20
?Kalimantan Tengah
42
9.3
86
5.0
193
4.54
321
0
0.00
0
0.00
0
0.00
0
0
0.00
1
0.06
0
0.00
1
151
0.80
?21
?Kalimantan Selatan
114
15.9
358
15.8
618
9.56
1,090
0
0.00
3
0.13
15
0.23
18
4
0.56
1
0.04
8
0.12
13
26
0.10
?22
?Kalimantan Timur
46
7.1
117
5.7
142
2.56
305
1
0.15
2
0.10
0
0.00
3
0
0.00
10
0.49
14
0.25
24
307
1.20
?23
?Sulawesi Utara
26
5.8
62
4.8
57
1.5
145
0
0.00
0
0.00
0
0.00
0
0
0.00
0
0.00
0
0.00
0
35
0.20
?24
?Sulawesi Tengah
56
10.6
167
9.0
91
1.8
314
1
0.19
0
0.00
0
0.00
1
4
0.76
15
0.81
4
0.08
23
579
2.50
?25
?Sulawesi Selatan
20
1.1
169
2.6
98
0.55
287
1
0.05
1
0.02
5
0.03
7
19
1.03
39
0.60
60
0.34
118
985
1.20
?26
?Sulawesi Tenggara
10
2.0
12
0.7
18
0.39
40
0
0.00
0
0.00
2
0.04
2
6
1.19
13
0.71
0
0.00
19
101
0.50
?27
?Gorontalo
16
8.0
91
13.4
59
3.14
166
1
0.50
2
0.29
0
0.00
3
0
0.00
0
0.00
0
0.00
0
205
2.40
?28
?Maluku
12
3.4
30
2.9
24
0.79
66
0
0.00
1
0.10
0
0.00
1
3
0.00
15
1.45
4
0.13
22
123
1.00
?29
?Maluku Utara
0
0.0
2
0.3
14
0.71
16
0
0.00
0
0.00
0
0.00
0
0
0.00
5
0.72
2
0.10
7
0
0.00
?30
?Papua
16
2.7
42
2
46
0.84
104
0
0.00
0
0.00
0
0.00
0
0
0.00
0
0.00
0
0.00
0
8
0.00
Indonesia
3,203
6.8
8,403
5.4
8,993
2.15
20,599
31
0.07
70
0.05
94
0.02
195
565
1.20
?1,261
0.81
962
0.23
?2,788
29,597
1.40
Sumber: Ditjen PPM-PL Depkes RI
Keterangan : AI = angka Insidens
JUMLAH KASUS DAN ANGKA INSIDENS PENYAKIT HEPATITIS PER 10.000 PENDUDUK?
MENURUT PROVINSI TAHUN 2000 - 2003??
No.
Provinsi
2000
2001
2002
2003
Kasus
AI
Kasus
AI
Kasus
AI
Kasus
AI
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
???? 1
?Nanggroe Aceh Darussalam
-
-
948
2.20
649
1.50
541
1.30
649
???? 2
?Sumatera Utara
2,922
2.37
7,623
6.20
1,288
1.00
1,636
1.30
1288
???? 3
?Sumatera Barat
-
-
241
0.50
-
-
80
0.20
0
???? 4
?Riau
-
-
263
0.60
202
0.50
177
0.30
202
???? 5
?Jambi
-
-
103
0.40
42
0.20
125
0.50
42
???? 6
?Sumatera Selatan
-
-
46
0.10
309
0.40
746
1.00
309
???? 7
?Bengkulu
-
-
363
2.20
313
1.90
53
0.30
313
???? 8
?Lampung
31
0.04
1,518
2.10
1,379
1.90
14,491
20.60
0
???? 9
?Kepulauan Bangka Belitung
-
-
-
-
-
-
29
0.30
1379
?? 10
?DKI Jakarta
288
0.29
86
0.10
340
0.30
1,004
1.20
340
?? 11
?Jawa Barat
55
0.01
8,094
1.80
2,580
0.60
2,690
0.70
0
?? 12
?Jawa Tengah
-
-
570
0.20
-
-
283
0.10
2580
?? 13
?DI Yogyakarta
-
-
217
0.70
-
-
193
0.60
0
?? 14
?Jawa Timur
-
-
2,831
0.80
1,265
0.40
2,135
0.60
0
?? 15
?Banten
-
-
33
-
-
-
1,341
1.60
1265
?? 16
?Bali
-
-
626
2.00
165
0.50
317
1.00
560
?? 17
?Nusa Tenggara Barat
62
0.15
-
-
-
-
132
0.30
477
?? 18
?Nusa Tenggara Timur
13,711
34.44
332
0.80
242
0.60
215
0.50
58
?? 19
?Kalimantan Barat
90
0.22
338
0.80
560
1.40
889
2.10
84
?? 20
?Kalimantan Tengah
377
2.05
386
2.10
477
2.60
151
0.80
135
?? 21
?Kalimantan Selatan
-
-
138
0.40
58
0.20
26
0.10
124
?? 22
?Kalimantan Timur
-
-
197
0.70
84
0.30
307
1.20
200
?? 23
?Sulawesi Utara
-
-
164
0.60
135
0.50
35
0.20
2288
?? 24
?Sulawesi Tengah
-
-
276
1.20
200
0.90
579
2.50
320
?? 25
?Sulawesi Selatan
-
-
877
1.10
2,288
2.70
985
1.20
165
?? 26
?Sulawesi Tenggara
3
0.02
423
2.30
320
1.80
101
0.50
0
?? 27
?Gorontalo
-
-
61
-
124
-
205
2.40
242
?? 28
?Maluku
-
-
-
-
-
-
123
1.00
0
?? 29
?Maluku Utara
-
-
-
-
9
-
-
-
9
?? 30
?Papua
-
-
-
-
94
0.40
8
-
94
Indonesia
17,539
0.83
26,754
1.30
13,123
0.60
29,597
1.40
13123
Sumber : Ditjen PPM-PL Depkes RI
Keterangan : (-) tidak ada data
????????????????????? AI = Angka Insidens
FREKUENSI KLB MENURUT JENIS PENYAKIT DI INDONESIA?
TAHUN 2003
No.
Penyakit
Frekuensi
Kasus
Meninggal
CFR (%)
(1)
(2)
(3)
(4)
(5)
(6)
????? 1
?Diare
92
3,865
113
2.92
????? 2
?DHF
260
2,218
77
3.47
????? 3
?Campak
89
2,914
10
0.34
????? 4
?Difteri
54
86
20
23.26
????? 5
?Pertusis
5
124
0
0,00
????? 6
?Tetanus
1
2
2
100.00
????? 7
?Malaria
60
5,571
197
3.54
????? 8
?Hepatitis
41
1,917
0
0,00
????? 9
?Meningitis
3
4
1
25.00
??? 10
?Rabies
57
139
36
25.90
??? 11
?Anthrax
4
34
2
5.88
??? 12
?Keracunan Makanan
73
2,317
12
0.52
??? 13
?HIV/AIDS
2
4
1
25.00
??? 14
?Demam Kuning
2
96
26
27.08
??? 15
?Cacar Air
5
268
0
0,00
??? 16
?Parotitis
2
105
0
0,00
??? 17
?Keracunan
13
368
8
2.17
??? 18
?HFMD
4
5
0
0,00
??? 19
?Cikungunya
91
4,084
0
0,00
??? 20
?Leptospirosis
8
9
3
33.33
??? 21
?Thypoid
2
21
1
4.76
??? 22
?Marasmus
7
8
0
0,00
??? 23
?Lain-lain
22
86
4
4.65
Total
897
24,245
513
2.12
Sumber: Ditjen PPM-PL Depkes RI
JUMLAH PENDERITA, CASE FATALITY RATE (%), DAN INCIDENCE RATE PENYAKIT DEMAM BERDARAH DENGUE (DBD/DHF)
MENURUT PROVINSI TAHUN 2000 - 2003
No.
Provinsi
Tahun 2000
Tahun 2001
???????? Tahun 2002
Tahun 2003
P
CFR
IR
P
CFR
IR
P
CFR
IR
P
CFR
IR
(1)
(2)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
???? 1
?Nanggroe Aceh Darussalam
64
11
1.54
35
3
0.80
92
8.7
2.13
128
3.1
2.76
???? 2
?Sumatera Utara
96
0
0.86
138
0
1.23
348
3.7
2.80
878
2.7
7.07
???? 3
?Sumatera Barat
83
0
2.10
185
0
4.34
623
1.6
13.74
292
0.7
6.88
???? 4
?Riau
390
3
9.21
1,324
2
29.69
978
0.8
19.42
715
0.7
13.98
???? 5
?Jambi
131
5
5.10
129
4
5.21
272
4.0
10.71
80
2.5
2.83
???? 6
?Sumatera Selatan
1,211
2
18.59
1,890
1
27.86
1,406
1.8
19.71
1,403
2.1
17.87
???? 7
?Bengkulu
17
0
1.10
17
6
1.06
14
0.0
0.91
2
0.0
0.13
???? 8
?Lampung
66
6
0.91
228
4
3.10
197
5.1
3.43
624
2.6
9.29
???? 9
?Kepulauan Bangka Belitung
-
-
-
-
-
-
29
3.4
3.21
241
4.1
26.68
?? 10
?DKI Jakarta
3,751
1
41.26
8,661
0
78.92
5,750
0.9
66.86
14,071
0.4
125.09
?? 11
?Jawa Barat
2,283
3
5.38
5,152
2
11.84
4,817
1.3
13.56
8,683
2.1
23.64
?? 12
?Jawa Tengah
4,907
2
15.09
5,001
2
15.37
6,357
1.6
19.09
8,490
2.3
25.51
?? 13
?DI Yogyakarta
492
2
14.40
917
1
26.84
992
1.0
28.57
1,553
2.3
47.09
?? 14
?Jawa Timur
3,247
1
9.25
4,224
1
12.04
5,308
1.3
15.04
4,216
1.4
11.94
?? 15
?Banten
-
-
-
-
-
-
713
0.7
8.00
700
3.6
8.17
?? 16
?Bali
757
1
25.34
199
1
6.44
3,986
0.3
130.87
2,364
0.3
76.78
?? 17
?Nusa Tenggara Barat
34
6
0.89
72
6
1.84
232
1.3
5.91
196
4.6
5.06
?? 18
?Nusa Tenggara Timur
118
0
3.07
60
3
1.52
24
4.2
0.63
260
3.2
6.34
?? 19
?Kalimantan Barat
1,393
4
35.06
806
31
19.57
1,910
1.6
49.97
349
2.0
9.13
?? 20
?Kalimantan Tengah
20
0
1.20
30
10
17.10
72
2.8
4.00
300
3.0
16.36
?? 21
?Kalimantan Selatan
91
7
2.94
121
6
5.64
365
0.3
17.04
178
3.4
7.47
?? 22
?Kalimantan Timur
253
1
10.51
1,423
2
58.17
2,011
2.0
80.08
1,926
1.5
77.32
?? 23
?Sulawesi Utara
1,139
4
40.85
1,105
3
38.89
974
1.4
47.47
369
1.3
15.75
?? 24
?Sulawesi Tengah
31
7
1.57
178
6
8.67
81
2.5
3.27
184
1.0
7.47
?? 25
?Sulawesi Selatan
428
2
5.31
1,323
2
15.03
2,408
1.6
31.71
2,636
1.5
31.41
?? 26
?Sulawesi Tenggara
0
0
0.00
11
0
0.63
51
0.0
2.91
43
2.3
2.45
?? 27
?Gorontalo
-
-
-
-
-
-
4
0.0
0.31
30
0.0
3.54
?? 28
?Maluku
3
0
0.14
0
0
0.00
0
0.0
0.00
0
0.0
0.00
?? 29
?Maluku Utara
-
-
-
-
-
-
63
3.2
7.20
2
1.0
0.23
?? 30
?Papua
123
6
6.04
214
2
10.34
300
1.0
14.19
603
0.8
29.13
Indonesia
21,134
2
10.17
33,443
1.4
15.99
40,377
1.3
19.24
51,516
1.5
23.87
Sumber: Ditjen PPM-PL, Depkes RI
Keterangan : (-) tidak ada data
????????????????????? IR (Incidens Rate) per 100.000 penduduk
JUMLAH KABUPATEN/KOTA YANG TERJANGKIT PENYAKIT DEMAM BERDARAH DENGUE
MENURUT PROVINSI DI INDONESIA TAHUN 2001 - 2003
No.
Provinsi
Jumlah Kabupaten? /Kota
Kabupaten/Kota Terjangkit DBD
2001
2002
2003
Jumlah
%
Jumlah
%
Jumlah
%
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
???? 1
?Nanggroe Aceh Darussalam
20
7
35.00
9
45.00
8
40.00
???? 2
?Sumatera Utara
23
13
56.52
15
65.22
14
60.87
???? 3
?Sumatera Barat
16
6
37.50
4
25.00
3
18.75
???? 4
?Riau
16
10
62.50
13
81.25
12
75.00
???? 5
?Jambi
10
7
70.00
7
70.00
4
40.00
???? 6
?Sumatera Selatan
11
7
37.50
9
81.82
7
63.64
???? 7
?Bengkulu
7
4
62.50
4
57.14
1
14.29
???? 8
?Lampung
10
9
70.00
9
90.00
8
80.00
???? 9
?Kepulauan Bangka Belitung
7
3
63.64
2
28.57
3
42.86
?? 10
?DKI Jakarta
6
5
57.14
5
83.33
5
83.33
?? 11
?Jawa Barat
25
22
90.00
24
96.00
24
96.00
?? 12
?Jawa Tengah
35
33
42.86
35
100.00
34
97.14
?? 13
?DI Yogyakarta
5
5
83.33
5
100.00
5
100.00
?? 14
?Jawa Timur
38
37
88.00
38
100.00
38
100.00
?? 15
?Banten
6
6
94.29
6
100.00
3
50.00
?? 16
?Bali
9
8
100.00
9
100.00
8
88.89
?? 17
?Nusa Tenggara Barat
8
6
97.37
7
87.50
6
75.00
?? 18
?Nusa Tenggara Timur
16
3
100.00
1
6.25
3
18.75
?? 19
?Kalimantan Barat
10
8
88.89
8
80.00
8
80.00
?? 20
?Kalimantan Tengah
14
6
75.00
6
42.86
5
35.71
?? 21
?Kalimantan Selatan
13
9
18.75
5
38.46
8
61.54
?? 22
?Kalimantan Timur
13
10
80.00
10
76.92
12
92.31
?? 23
?Sulawesi Utara
8
5
42.86
4
50.00
4
50.00
?? 24
?Sulawesi Tengah
9
2
69.23
2
22.22
5
55.56
?? 25
?Sulawesi Selatan
28
20
76.92
17
60.71
18
64.29
?? 26
?Sulawesi Tenggara
7
2
62.50
3
42.86
3
42.86
?? 27
?Gorontalo
5
3
22.22
2
40.00
2
40.00
?? 28
?Maluku
5
0
71.43
0
0.00
0
0.00
?? 29
?Maluku Utara
8
2
28.57
2
25.00
2
25.00
?? 30
?Papua
28
5
60.00
3
10.71
4
14.29
Indonesia
416
263
63.22
264
63.46
257
61.78
Sumber: Ditjen PPM-PL, Depkes RI
--
Shigenoi Haruki
Propello Innovations Private Limited,the innovations of modern technology brand products like kitchen chimney in kolkata,kitchen chimney dealers in kolkata.we also provide (RO)reverse osmosis water purifier in kolkata ,orrisa & guwahati.
ReplyDeletewater purifiers in orissa
You made some good points there. I did a search on the topic and found most people will agree with your blog.
ReplyDeleteMalaria Detection Microscope africa
I am bold enough among many others to state that there is now a potent cure to this sickness but many are unaware of it. I discovered that I was infected with the virus 3 months ago, after a medical check-up. My doctor told me and I was shocked, confused and felt like my world has crumbled. I was dying slowly due to the announcement of my medical practitioner but he assured me that I could leave a normal life if I took my medications (as there was no medically known cure to Herpes). I went from churches to churches but soon found that my case needed urgent attention as I was growing lean due to fear of dying anytime soon. In a bid to look for a lasting solution to my predicament, I sought for solutions from the herbal world. I went online and searched for every powerful trado-medical practitioner that I could severe, cos I heard that the African Herbs had a cure to the Herpes syndrome. It was after a little time searching the web that I came across one Dr Itua(A powerful African Herbal Doctor), who offered to help me at a monetary fee. I had to comply as this was my final bus-stop to receiving a perfect healing. My last resolve was to take my life by myself, should this plan fail. At last it worked out well. He gave me some steps to follow and I meticulously carried out all his instructions. Last month, to be precise, I went back to the hospital to conduct another test and to my amazement, the results showed that negative,Dr Itua Can As Well Cure The Following Desease…Cancer,Hiv,Herpes,Shingles, Hepatitis B,Liver Inflammatory,Diabetis,Fribroid,Parkinson's,Alzheimer’s disease,Bechet’s disease,Crohn’s disease,Cushing’s disease,Heart failure,Multiple Sclerosis,HypertensionFatal Familial Insomnia Factor V Leiden Mutation ,Epilepsy Dupuytren's disease,Desmoplastic small-round-cell tumor Diabetes ,Coeliac disease,Creutzfeldt–Jakob disease,Cerebral Amyloid Angiopathy, Ataxia,Arthritis,Amyotrophic Lateral Scoliosis,Autism,Fibromyalgia,Fluoroquinolone ToxicitySyndrome Fibrodysplasia Ossificans ProgresSclerosis,Seizures,Adrenocortical carcinoma.Asthma,Allergic diseases,,Copd,Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Lung disease.Enlarged prostate,Osteoporosis.
ReplyDeleteDementia.,Lyme Disease,,Non Hodgkin Lymphoma,Skin Cancer,Uterine Cancer,Prostate Cancer Dercum,Lupus,Hpv,Weak Erection,Infertility,fibromyalgia,Chronic Diarrhea,Get Your Ex Back,Als,SYPHILLIS,Colo-Rectal Cancer,Blood Cancer,Breast CANCER,Lung Cancer,Prostate Cancer,Autism,Brain Cancer,Genetic disease,Epilepsy, Parkinson's disease..You can free yourself of this Herpes virus by consulting this great African Herbal Doctor via this e-mail: drituaherbalcenter@gmail.com / . or call and whatsapp him on +2348149277967 He will help you and his herb medication is sure. he has the cure on all disease .You can talk to me on INSTAGRAM..tashamoore219.