Malaria
| Etiology |
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- Nearly all cases of Malaria are caused by infection with one of four plasmodial species: P. falciparum, P. vivax, P. ovale, and P. malariae. Infection with P. falciprum is the most virulent and is responsible for nearly all malarial deaths.
| Epidemiology |
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- Malaria has now been eliminated in most developed countries and is largely observed in tropical areas, especially in sub-Saharan Africa. Over 1 million people die each year from Malaria and it is by far the most common parasitic disease.
| Plasmodium Life Cycle |
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- Inoculation
- Plasmodia are introduced into the blood stream in their motile "Sporozoite" stage by the Anopheles mosquito during a blood meal.
- Hepatic Cycle
- Sporozoites travel via the bloodstream to the liver where they infect hepatocytes and replicate asexually. Hepatocytes will become swollen with replicating organisms which progress through "Trophozoite" and "Schizont" stages, ultimately maturing into "Merozoites". The trophozoite stage is a round form in which the nucleus replicates without cell division, ultimately forming the schizont which possesses a swollen mass of nuclei. Synthesis of cell membranes between each of these nuclei, forming separate cells, results in development of the merozoite. Eventually the swollen hepatocyte will burst, releasing thousands of merozoites into the blood stream which can either re-infect fresh hepatocytes or can go onto to the "Erythrocytic Cycle".
- Erythrocytic Cycle
- Most released merozoites infect erythrocytes where they replicate asexually and ultimately lyse the cell within 48-72hrs. Once again, the organism replicates by progressing through trophozoite and schizont stages, ultimately maturing into tens of merozoites which go on to infect new erythrocytes and replicate within them. Continued cycles of erythrocyte infection and lysis can result in extremely high loads of organism within the blood.
- Gametocytic Differentiation
- Some merozoites exit the Erythrocytic Cycle and differentiate into male and female "Gametocytes". These forms of the organism are transmissible to the Anopheles mosquito during a blood meal. Within the mosquito gut, the male and female gametocytes mate sexually and produce an oocyst. The oocyst eventually divides and differentiates into the sporozoite form which can then be inoculated into a new host
- Hypnozoites
- P. vivax and P. ovale possess a special "Hypnozoite" form which can develop in hepatocytes during the Hepatic Cycle. Hypnozoites do not replicate and can remain dormant for years until later reactivation. Consequently, P. vivax and P. ovale Malaria may undergo recrudescence months or years later.
| Diagnosis |
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- Although newer techniques are now available, malarial diagnosis is still largely based on microscopic examination of giemsa-stained erythrocytes. Young trophozoites are circular and possess a single, eccentrically located nucleus. As the trophozoites mature, they become increasingly amoeboid and the schizont appears as a mass of nuclei. The different plasmodial possess some unique features when infecting erythrocytes and this can be used to narrow diagnosis to a specific species.
| Pathogenesis |
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- Febrile Component
- Infection and lysis of RBCs by merozoites during the Erythrocytic Cycle releases enormous amounts of cellular debris that can enter the blood stream which is responsible for an intense febrile reaction by the body. In some cases, lysis occur synchronously across many RBCs, resulting in a pattern of febrile spikes and troughs.
- Erythrocytic Adherence
- Through mechanisms which are still not understood plasmodial species can synthesize and insert large proteins within the the membranes of the RBCs that they infect. These proteins change the morphology of the normally smooth RBC membrane to a knobby appearance which is much more adherent to vascular walls. The increased adherence of infected RBCs can cause occlusion and thrombosis of small vasculature within a variety of organs and lead to significant clinical consequences. RBC knobiness and adherence is most prominent during infections with P. falciparum, explaining the increased virulence of this species.
| Clinical Consequences |
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- For the vast majority of patients the course of ,alaria is uncomplicated and consists of a largely non-sepcific, febrile disease. However, a small fraction of patients (Less than 1%) go on to develop potentially life-threatening complications described in the following section. Following a variable incubation period individuals begin to feel mild constitutional symptoms such as malaise, headache, and myalgia. Eventually, a febrile component becomes prominent and may wax in regular intervals with spikes of fever and chills. Cyclic fever is much more common with P. vivax and P. ovale and may never occur with P. falciprum. Because of the significant burden of erythrocyte lysis, some individuals may develop anemia although this does not always occur. Some patients also develop hepatosplenomegaly or jaundice.
| Complications |
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- Life-threatening Malarial complications usually occur only in the context of P. falciparum infection. As mentioned in Pathogenesis, these are likely due to increased adherence of infected RBCs which result in occlusion of microvasculature in a variety of organs.
- Cerebral Malaria: Cerebral Malaria is fatal in a significant minority of individuals and is the result of a diffuse encephalopathy which manifests as somnolence, behavioral abnormalities, and eventually coma
- Hypoglycemia: A sequelae of reduced hepatic gluconeogenesis
- Pulmonary Edema: The pathogenesis is not known
- Acute Renal Failure: Probably due to obstruction of renal vasculature, resulting in ischemic acute tubular necrosis
| Immunity |
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- Immune System
- The host immune response to malaria is not fully understood although both cell-mediated and humoral immunity appear to be required. Although the immune system can eliminate the infection, it does not confer protection and reinfection is possible. However, previous infections appear to reduce the intensity of symptomology for each new infection.
- Genetic Protection
- Several genetic alleles that affect RBCs appear to confer increased protection against the organism and may explain the increased incidence of these alleles in those of African descent. For example, heterozyogosity for the Sickle Cell Trait provides increased protection against P. falciparum infection.
| Treatment |
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- Quinolines, artemisinin, and pyrimethamine can all be used to treat malaria. In general, P. malariae, P. vivax, and P. ovale are sensitive to chloroquine and this quinoline is the primary treatment. If susceptible, P. falicparum should also be treated with chloroquine; however, Chloroquine-resistant P. falciparum is now widespread. Chloroquine-resistant strains of P. falciparum are generally treated with an artemisinin derivative plus an additional quinoline, usually mefloquine. Importantly, primaquine is the primary drug used to eliminate dormant P. vivax and P. ovale hypnozoites in the liver to prevent later malarial recrudescence.