CHIKENPOX

Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases progressing to coma or death. It is widespread in tropical and subtropical regions, including much of Sub-Saharan Africa , Asia, and the Americas. Five species of Plasmodium can infect and be transmitted by humans. Severe disease is largely caused by Plasmodium falciparum while the disease caused by Plasmodium vivax , Plasmodium ovale ,[1] and Plasmodium malariae is generally a milder disease that is rarely fatal. Plasmodium knowlesi is a zoonosis that causes malaria in macaques but can also infect humans. [2] [3] Malaria transmission can be reduced by preventing mosquito bites by distribution of mosquito nets and insect repellents, or by mosquito- control measures such as spraying insecticides and draining standing water (where mosquitoes breed). Despite a clear need, no vaccine offering a high level of protection currently exists. Efforts to develop one are ongoing.[4] A number of medications are also available to prevent malaria in travelers to malaria-endemic countries (prophylaxis ). A variety of antimalarial medications are available. Severe malaria is treated with intravenous or intramuscular quinine or, since the mid-2000s, the artemisinin derivative artesunate,[5] which is superior to quinine in both children and adults.[6] Resistance has developed to several antimalarial drugs, most notably chloroquine.[7] There were an estimated 225 million cases of malaria worldwide in 2009. [8] An estimated 655,000 people died from malaria in 2010,[9] a 5% decrease from the 781,000 who died in 2009 according to the World Health Organization's 2011 World Malaria Report, accounting for 2.23% of deaths worldwide. [8] Ninety percent of malaria- related deaths occur in sub- Saharan Africa, with the majority of deaths being young children. Plasmodium falciparum, the most severe form of malaria, is responsible for the vast majority of deaths associated with the disease.[10] Malaria is commonly associated with poverty, and can indeed be a cause of poverty [11] and a major hindrance to economic development . Signs and symptoms Main symptoms of malaria. [12] Typical fever patterns of malaria Symptoms of malaria include fever , shivering , arthralgia (joint pain), vomiting , anemia (caused by hemolysis ), jaundice, hemoglobinuria, retinal damage,[13] and convulsions . The classic 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, and every three days for P. malariae.[14]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 that may be related to high intracranial pressure, children with malaria frequently exhibit abnormal posturing, a sign indicating severe brain damage. [15] 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. [16][17] Cerebral malaria is associated with retinal whitening, [18] which may be a useful clinical sign in distinguishing malaria from other causes of fever. [19] Severe malaria is almost exclusively caused by Plasmodium falciparum infection, and usually arises 6– 14 days after infection. [20] 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 is a feature of 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. [20] In the most severe cases of the disease, fatality rates can exceed 20%, even with intensive care and treatment. [21] 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.[22] Over the longer term, developmental impairments have been documented in children who have suffered episodes of severe malaria. [23] Cause A Plasmodium sporozoite traverses the cytoplasm of a mosquito midgut epithelial cell in this false-color electron micrograph. Malaria parasites are members of the genus Plasmodium (phylum Apicomplexa ). In humans malaria is caused by P. falciparum, P. malariae, P. ovale , P. vivax and P. knowlesi .[24][25] While P. vivax is responsible for the largest number of malaria infections worldwide, infections by P. falciparum account for about 90% of the deaths from malaria.[26] Parasitic Plasmodium species also infect birds, reptiles, monkeys, chimpanzees and rodents.[27] There have been documented human infections with several simian species of malaria; however, with the exception of P. knowlesi, these are mostly of limited public health importance.[28] Malaria parasites contain apicoplasts, an organelle usually found in plants, complete with their own functioning genomes. These apicoplast are thought to have originated through the endosymbiosis of algae[29] and play a crucial role in various aspects of parasite metabolism e.g. fatty acid bio- synthesis. [30] To date, 466 proteins have been found to be produced by apicoplasts [31] and these are now being looked at as possible targets for novel anti-malarial drugs. Life cycle The parasite's secondary hosts are humans and other vertebrates. Female mosquitoes of the Anopheles genus are the primary, i.e. definitive hosts and act as transmission vectors . 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's gut. This produces an ookinete that penetrates the gut lining and produces an oocyst in the gut wall. When the oocyst ruptures, it releases sporozoites that migrate through the mosquito's body to the salivary glands, where they are then ready to infect a new human host. This type of transmission is occasionally referred to as anterior station transfer.[32] The sporozoites are injected into the skin, alongside saliva, when the mosquito takes a subsequent blood meal. Only female mosquitoes feed on blood while male mosquitoes feed on plant nectar,[33] 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.[34] Recurrent malaria Malaria recurs after treatment for three reasons. Recrudescence occurs when parasites are not cleared by treatment, whereas reinfection indicates complete clearance with new infection established from a separate infective mosquito bite; both can occur with any malaria parasite species. Relapse is specific to P. vivax and P. ovale and involves re- emergence of blood-stage parasites from latent parasites (hypnozoites) in the liver. Describing a case of malaria as cured by observing the disappearance of parasites from the bloodstream can, therefore, be deceptive. The longest incubation period reported for a P. vivax infection is 30 years. [20] 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).[35] Pathogenesis Further information: Plasmodium falciparum biology The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. 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, where they develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. Sexual forms (gametocytes) are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle. Malaria develops via two phases: an exoerythrocytic and an erythrocytic phase. The exoerythrocytic phase involves infection of the hepatic system, or liver, whereas the erythrocytic phase involves infection of the erythrocytes, or red blood cells. 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 minutes of being introduced into the human host, the sporozoites infect hepatocytes , multiplying asexually and asymptomatically for a period of 8–30 days. [36] 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. [36] The parasite escapes from the liver undetected by wrapping itself in the cell membrane of the infected host liver cell. [37] 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. [38] 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.[39] 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.[40] Micrograph of a placenta from a stillbirth due to maternal malaria. H&E stain. Red blood cells are anuclear; blue/black staining in bright red structures (red blood cells) indicate foreign nuclei from the parasites Although the red blood cell surface adhesive proteins (called PfEMP1, for 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 even more variants within whole parasite populations.[39] 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. (Because sexual reproduction of the parasite defines the definitive host , the mosquito is the definitive host, whereas humans are the intermediate host.) New sporozoites develop and travel to the mosquito's salivary gland, completing the cycle. Pregnant women are especially attractive to the mosquitoes, [41] and malaria in pregnant women is an important cause of stillbirths, infant mortality and low birth weight, [42] particularly in P. falciparum infection, but also in other species infection, such as P. vivax.