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    * Malaria *


    (Wikipedia) - Malaria Malaria ICD-10 ICD-9 OMIM DiseasesDB MedlinePlus eMedicine Patient UK MeSH
    Classification and external resources
    med/1385 emerg/305 ped/1357

    Malaria is a mosquito-borne infectious disease of humans and other animals caused by parasitic protozoans (a type of single cell microorganism) of the Plasmodium type. Malaria causes symptoms that typically include fever, fatigue, vomiting and headaches. In severe cases it can cause yellow skin, seizures, coma or death. These symptoms usually begin ten to fifteen days after being bitten. In those who have not been appropriately treated disease may recur months later. In those who have recently survived an infection, re-infection typically causes milder symptoms. This partial resistance disappears over months to years if there is no ongoing exposure to malaria.

    Commonly, the disease is transmitted by the bite of an infected female Anopheles mosquito. This bite introduces the parasites from the mosquito''s saliva into a person''s blood. The parasites then travel to the liver where they mature and reproduce. Five species of Plasmodium can infect and be spread by humans. Most deaths are caused by P. falciparum because P. vivax, P. ovale, and P. malariae generally cause a milder form of malaria. The species P. knowlesi rarely causes disease in humans. Malaria is typically diagnosed by the microscopic examination of blood using blood films, or with antigen-based rapid diagnostic tests. Methods that use the polymerase chain reaction to detect the parasite''s DNA have been developed, but are not widely used in areas where malaria is common due to their cost and complexity.

    The risk of disease can be reduced by preventing mosquito bites by using mosquito nets and insect repellents, or with mosquito-control measures such as spraying insecticides and draining standing water. Several medications are available to prevent malaria in travellers to areas where the disease is common. Occasional doses of the medication sulfadoxine/pyrimethamine are recommended in infants and after the first trimester of pregnancy in areas with high rates of malaria. Despite a need, no effective vaccine exists, although efforts to develop one are ongoing. The recommended treatment for malaria is a combination of antimalarial medications that includes an artemisinin. The second medication may be either mefloquine, lumefantrine, or sulfadoxine/pyrimethamine. Quinine along with doxycycline may be used if an artemisinin is not available. It is recommended that in areas where the disease is common, malaria is confirmed if possible before treatment is started due to concerns of increasing drug resistance. Resistance has developed to several antimalarial medications; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and resistance to artemisinin has become a problem in some parts of Southeast Asia.

    The disease is widespread in tropical and subtropical regions that are present in a broad band around the equator. This includes much of Sub-Saharan Africa, Asia, and Latin America. The World Health Organization estimates that in 2012, there were 207 million cases of malaria. That year, the disease is estimated to have killed between 473,000 and 789,000 people, many of whom were children in Africa. Malaria is commonly associated with poverty and has a major negative effect on economic development. In Africa it is estimated to result in losses of $12 billion USD a year due to increased healthcare costs, lost ability to work and effects on tourism.

    • 1 Signs and symptoms
      • 1.1 Complications
    • 2 Cause
      • 2.1 Life cycle
      • 2.2 Recurrent malaria
    • 3 Pathophysiology
      • 3.1 Genetic resistance
      • 3.2 Liver dysfunction
    • 4 Diagnosis
      • 4.1 Classification
    • 5 Prevention
      • 5.1 Mosquito control
      • 5.2 Other methods
      • 5.3 Medications
    • 6 Treatment
      • 6.1 Resistance
    • 7 Prognosis
    • 8 Epidemiology
    • 9 History
    • 10 Society and culture
      • 10.1 Economic impact
      • 10.2 Counterfeit and substandard drugs
      • 10.3 War
      • 10.4 Eradication efforts
    • 11 Research
    • 12 Other animals
    • 13 References
    • 14 Further reading
    • 15 External links

    Signs and symptomsMain symptoms of malaria

    The signs and symptoms of malaria typically begin 8–25 days following infection; however, symptoms may occur later in those who have taken antimalarial medications as prevention. Initial manifestations of the disease—common to all malaria species—are similar to flu-like symptoms, and can resemble other conditions such as septicemia, gastroenteritis, and viral diseases. The presentation may include headache, fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, and convulsions.


    Severe malaria is usually caused by P. falciparum (often referred to as falciparum malaria). Symptoms of falciparum malaria arise 9–30 days after infection. Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures, or coma.



    Infection with P. falciparum may result in cerebral malaria, a form of severe malaria that involves encephalopathy. It is associated with retinal whitening, which may be a useful clinical sign in distinguishing malaria from other causes of fever. Splenomegaly, severe headache, hepatomegaly (enlarged liver), hypoglycemia, and hemoglobinuria with renal failure may occur.


    Cause Main article: Plasmodium

    Malaria parasites belong to the genus Plasmodium (phylum Apicomplexa). In humans, malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax and P. knowlesi. Among those infected, P. falciparum is the most common species identified (~75%) followed by P. vivax (~20%). Although P. falciparum traditionally accounts for the majority of deaths, recent evidence suggests that P. vivax malaria is associated with potentially life-threatening conditions about as often as with a diagnosis of P. falciparum infection. P. vivax proportionally is more common outside of Africa. There have been documented human infections with several species of Plasmodium from higher apes; however, except for P. knowlesi—a zoonotic species that causes malaria in macaques—these are mostly of limited public health importance.




    Other merozoites develop into immature gametocytes, which are the precursors of male and female gametes. When a fertilised mosquito bites an infected person, gametocytes are taken up with the blood and mature in the mosquito gut. The male and female gametocytes fuse and form an ookinete—a fertilized, motile zygote. Ookinetes develop into new sporozoites that migrate to the insect''s salivary glands, ready to infect a new vertebrate host. The sporozoites are injected into the skin, in the saliva, when the mosquito takes a subsequent blood meal.


    Recurrent malaria

    Symptoms of malaria can recur after varying symptom-free periods. Depending upon the cause, recurrence can be classified as either recrudescence, relapse, or reinfection. Recrudescence is when symptoms return after a symptom-free period. It is caused by parasites surviving in the blood as a result of inadequate or ineffective treatment. Relapse is when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozoites in liver cells. Relapse commonly occurs between 8–24 weeks and is commonly seen with P. vivax and P. ovale infections. P. vivax malaria cases in temperate areas often involve overwintering by hypnozoites, with relapses beginning the year after the mosquito bite. Reinfection means the parasite that caused the past infection was eliminated from the body but a new parasite was introduced. Reinfection cannot readily be distinguished from recrudescence, although recurrence of infection within two weeks of treatment for the initial infection is typically attributed to treatment failure. People may develop some immunity when exposed to frequent infections.


    Malaria infection develops via two phases: one that involves the liver (exoerythrocytic phase), and one that involves red blood cells, or erythrocytes (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 where they infect hepatocytes, multiplying asexually and asymptomatically for a period of 8–30 days.




    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. The blockage of the microvasculature causes symptoms such as in placental malaria. Sequestered red blood cells can breach the blood–brain barrier and cause cerebral malaria.

    Genetic resistance Main article: Genetic resistance to malaria



    Liver dysfunction


    Diagnosis Main article: Diagnosis of malariaThe blood film is the gold standard for malaria diagnosis.Ring-forms and gametocytes of Plasmodium falciparum in human blood





    Malaria is classified into either "severe" or "uncomplicated" by the World Health Organization (WHO). It is deemed severe when any of the following criteria are present, otherwise it is considered uncomplicated.

    • Decreased consciousness
    • Significant weakness such that the person is unable to walk
    • Inability to feed
    • Two or more convulsions
    • Low blood pressure (less than 70 mmHg in adults and 50 mmHg in children)
    • Breathing problems
    • Circulatory shock
    • Kidney failure or hemoglobin in the urine
    • Bleeding problems, or hemoglobin less than 50 g/L (5 g/dL)
    • Pulmonary oedema
    • Blood glucose less than 2.2 mmol/L (40 mg/dL)
    • Acidosis or lactate levels of greater than 5 mmol/L
    • A parasite level in the blood of greater than 100,000 per microlitre (µL) in low-intensity transmission areas, or 250,000 per µL in high-intensity transmission areas





    Mosquito control Further information: Mosquito controlMan spraying kerosene oil in standing water, Panama Canal Zone 1912

    Vector control refers to methods used to decrease malaria by reducing the levels of transmission by mosquitoes. For individual protection, the most effective insect repellents are based on DEET or picaridin. Insecticide-treated mosquito nets (ITNs) and indoor residual spraying (IRS) have been shown to be highly effective in preventing malaria among children in areas where malaria is common. Prompt treatment of confirmed cases with artemisinin-based combination therapies (ACTs) may also reduce transmission.

    Walls where indoor residual spraying of DDT has been applied. The mosquitoes remain on the wall until they fall down dead on the floor.A mosquito net in use.

    Mosquito nets help keep mosquitoes away from people and reduce infection rates and transmission of malaria. Nets are not a perfect barrier and are often treated with an insecticide designed to kill the mosquito before it has time to find a way past the net. Insecticide-treated nets are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. Between 2000 and 2008, the use of ITNs saved the lives of an estimated 250,000 infants in Sub-Saharan Africa. About 13% of households in Sub-Saharan countries own ITNs. In 2000, 1.7 million (1.8%) African children living in areas of the world where malaria is common were protected by an ITN. That number increased to 20.3 million (18.5%) African children using ITNs in 2007, leaving 89.6 million children unprotected. An increased percentage of African households (31%) are estimated to own at least one ITN in 2008. Most nets are impregnated with pyrethroids, a class of insecticides with low toxicity. They are most effective when used from dusk to dawn. It is recommended to hang a large "bed net" above the center of a bed and either tuck the edges under the mattress or make sure it is large enough such that it touches the ground.

    Indoor residual spraying is the spraying of insecticides on the walls inside a home. After feeding, many mosquitoes rest on a nearby surface while digesting the bloodmeal, so if the walls of houses have been coated with insecticides, the resting mosquitoes can be killed before they can bite another person and transfer the malaria parasite. As of 2006, the World Health Organization recommends 12 insecticides in IRS operations, including DDT and the pyrethroids cyfluthrin and deltamethrin. This public health use of small amounts of DDT is permitted under the Stockholm Convention, which prohibits its agricultural use. One problem with all forms of IRS is insecticide resistance. Mosquitoes affected by IRS tend to rest and live indoors, and due to the irritation caused by spraying, their descendants tend to rest and live outdoors, meaning that they are less affected by the IRS.


    Other methods

    Community participation and health education strategies promoting awareness of malaria and the importance of control measures have been successfully used to reduce the incidence of malaria in some areas of the developing world. Recognizing the disease in the early stages can stop the disease from becoming fatal. Education can also inform people to cover over areas of stagnant, still water, such as water tanks that are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people. This is generally used in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas. Intermittent preventive therapy is another intervention that has been used successfully to control malaria in pregnant women and infants, and in preschool children where transmission is seasonal.

    Medications Main article: Malaria prophylaxis

    There are a number of drugs that can help prevent malaria while travelling in areas where it exists. Most of these drugs are also sometimes used in treatment. Chloroquine may be used where the parasite is still sensitive. Because most Plasmodium is resistant to one or more medications, one of three medications—mefloquine (Lariam), doxycycline (available generically), or the combination of atovaquone and proguanil hydrochloride (Malarone)—is frequently needed. Doxycycline and the atovaquone and proguanil combination are the best tolerated; mefloquine is associated with death, suicide, and neurological and psychiatric symptoms.

    The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before arriving and continue taking them for four weeks after leaving (except for atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward). The use of preventative drugs is often not practical for those who live in areas where malaria exists, and their use is usually only in short-term visitors and travellers. This is due to the cost of the drugs, side effects from long-term use, and the difficulty in obtaining anti-malarial drugs outside of wealthy nations. The use of preventative drugs where malaria-bearing mosquitoes are present may encourage the development of partial resistance. An exception to this is during pregnancy when taking medication to prevent malaria has been found to improve the weight of the baby at birth and decrease the risk of anemia in the mother.



    Uncomplicated malaria may be treated with oral medications. The most effective treatment for P. falciparum infection is the use of artemisinins in combination with other antimalarials (known as artemisinin-combination therapy, or ACT), which decreases resistance to any single drug component. These additional antimalarials include: amodiaquine, lumefantrine, mefloquine or sulfadoxine/pyrimethamine. Another recommended combination is dihydroartemisinin and piperaquine. ACT is about 90% effective when used to treat uncomplicated malaria. To treat malaria during pregnancy, the WHO recommends the use of quinine plus clindamycin early in the pregnancy (1st trimester), and ACT in later stages (2nd and 3rd trimesters). In the 2000s (decade), malaria with partial resistance to artemisins emerged in Southeast Asia.




    Drug resistance poses a growing problem in 21st-century malaria treatment. Resistance is now common against all classes of antimalarial drugs save the artemisinins. Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world. Malaria strains found on the CambodiaThailand border are resistant to combination therapies that include artemisinins, and may therefore be untreatable. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype. Resistance to artemisinin has been detected in Cambodia, Myanmar, Thailand, and Vietnam, and there has been emerging resistance in Laos.

    PrognosisDisability-adjusted life year for malaria per 100,000 inhabitants in 2004
       no data    <10    0–100    100–500    500–1000   1000–1500   1500–2000   2000–2500   2500–2750   2750–3000   3000–3250   3250–3500    ≥3500

    When properly treated, people with malaria can usually expect a complete recovery. However, severe malaria can progress extremely rapidly and cause death within hours or days. In the most severe cases of the disease, fatality rates can reach 20%, even with intensive care and treatment. Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria. Chronic infection without severe disease can occur in an immune-deficiency syndrome associated with a decreased responsiveness to Salmonella bacteria and the Epstein–Barr virus.

    During childhood, malaria causes anemia during a period of rapid brain development, and also direct brain damage resulting from cerebral malaria. Some survivors of cerebral malaria have an increased risk of neurological and cognitive deficits, behavioural disorders, and epilepsy. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups.

    EpidemiologyDistribution of malaria in the world: ♦ Elevated occurrence of chloroquine- or multi-resistant malaria ♦ Occurrence of chloroquine-resistant malaria ♦ No Plasmodium falciparum or chloroquine-resistance ♦ No malaria

    The WHO estimates that in 2010 there were 219 million cases of malaria resulting in 660,000 deaths. Others have estimated the number of cases at between 350 and 550 million for falciparum malaria and deaths in 2010 at 1.24 million up from 1.0 million deaths in 1990. The majority of cases (65%) occur in children under 15 years old. About 125 million pregnant women are at risk of infection each year; in Sub-Saharan Africa, maternal malaria is associated with up to 200,000 estimated infant deaths yearly. There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States. About 900 people died from the disease in Europe between 1993 and 2003. Both the global incidence of disease and resulting mortality have declined in recent years. According to the WHO, deaths attributable to malaria in 2010 were reduced by over a third from a 2000 estimate of 985,000, largely due to the widespread use of insecticide-treated nets and artemisinin-based combination therapies.

    Malaria is presently endemic in a broad band around the equator, in areas of the Americas, many parts of Asia, and much of Africa; in Sub-Saharan Africa, 85–90% of malaria fatalities occur. An estimate for 2009 reported that countries with the highest death rate per 100,000 of population were Ivory Coast (86.15), Angola (56.93) and Burkina Faso (50.66). A 2010 estimate indicated the deadliest countries per population were Burkina Faso, Mozambique and Mali. The Malaria Atlas Project aims to map global endemic levels of malaria, providing a means with which to determine the global spatial limits of the disease and to assess disease burden. This effort led to the publication of a map of P. falciparum endemicity in 2010. As of 2010, about 100 countries have endemic malaria. Every year, 125 million international travellers visit these countries, and more than 30,000 contract the disease.

    The geographic distribution of malaria within large regions is complex, and malaria-afflicted and malaria-free areas are often found close to each other. Malaria is prevalent in tropical and subtropical regions because of rainfall, consistent high temperatures and high humidity, along with stagnant waters in which mosquito larvae readily mature, providing them with the environment they need for continuous breeding. In drier areas, outbreaks of malaria have been predicted with reasonable accuracy by mapping rainfall. Malaria is more common in rural areas than in cities. For example, several cities in the Greater Mekong Subregion of Southeast Asia are essentially malaria-free, but the disease is prevalent in many rural regions, including along international borders and forest fringes. In contrast, malaria in Africa is present in both rural and urban areas, though the risk is lower in the larger cities.

    History Main articles: History of malaria and Mosquito-malaria theory


    References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China. Malaria may have contributed to the decline of the Roman Empire, and was so pervasive in Rome that it was known as the "Roman fever". Several regions in ancient Rome were considered at-risk for the disease because of the favourable conditions present for malaria vectors. This included areas such as southern Italy, the island of Sardinia, the Pontine Marshes, the lower regions of coastal Etruria and the city of Rome along the Tiber River. The presence of stagnant water in these places was preferred by mosquitoes for breeding grounds. Irrigated gardens, swamp-like grounds, runoff from agriculture, and drainage problems from road construction led to the increase of standing water.


    The term malaria originates from Medieval Italian: mala aria — "bad air"; the disease was formerly called ague or marsh fever due to its association with swamps and marshland. Malaria was once common in most of Europe and North America, where it is no longer endemic, though imported cases do occur.




    Artemisia annua, source of the antimalarial drug artemisin





    Society and culture See also: World Malaria Day Economic impactMalaria clinic in Tanzania

    Malaria is not just a disease commonly associated with poverty: some evidence suggests that it is also a cause of poverty and a major hindrance to economic development. Although tropical regions are most affected, malaria''s furthest influence reaches into some temperate zones that have extreme seasonal changes. The disease has been associated with major negative economic effects on regions where it is widespread. During the late 19th and early 20th centuries, it was a major factor in the slow economic development of the American southern states.



    Cerebral malaria is one of the leading causes of neurological disabilities in African children. Studies comparing cognitive functions before and after treatment for severe malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery. Consequently, severe and cerebral malaria have far-reaching socioeconomic consequences that extend beyond the immediate effects of the disease.

    Counterfeit and substandard drugs


    Another clinical and public health concern is the proliferation of substandard antimalarial medicines resulting from inappropriate concentration of ingredients, contamination with other drugs or toxic impurities, poor quality ingredients, poor stability and inadequate packaging. A 2012 study demonstrated that roughly one-third of antimalarial medications in Southeast Asia and Sub-Saharan Africa failed chemical analysis, packaging analysis, or were falsified.

    WarWorld War II poster


    Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. According to Joseph Patrick Byrne, "Sixty thousand American soldiers died of malaria during the African and South Pacific campaigns."



    Eradication efforts

    Several notable attempts are being made to eliminate the parasite from sections of the world, or to eradicate it worldwide. In 2006, the organization Malaria No More set a public goal of eliminating malaria from Africa by 2015, and the organization plans to dissolve if that goal is accomplished. Several malaria vaccines are in clinical trials, which are intended to provide protection for children in endemic areas and reduce the speed of transmission of the disease. As of 2012, The Global Fund to Fight AIDS, Tuberculosis and Malaria has distributed 230 million insecticide-treated nets intended to stop mosquito-borne transmission of malaria. The U.S.-based Clinton Foundation has worked to manage demand and stabilize prices in the artemisinin market. Other efforts, such as the Malaria Atlas Project, focus on analysing climate and weather information required to accurately predict the spread of malaria based on the availability of habitat of malaria-carrying parasites. The Malaria Policy Advisory Committee (MPAC) of the World Health Organization (WHO) was formed in 2012, "to provide strategic advice and technical input to WHO on all aspects of malaria control and elimination". In November 2013, WHO and the malaria vaccine funders group set a goal to develop vaccines designed to interrupt malaria transmission with the long-term goal of malaria eradication.



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