Malaria

General Goal: To know the major causes of malaria, the life cycle of these parasites, the most common modes of transmission and the major manifestations of this disease.

3. identify the most common means of transmission of this disease. Know the most common cause of malaria.

4. identify a patient with this disease based on clinical manifestations. There are other diseases with fever that come and go. Knowing the length, severity, and time period between fevers would be very helpful.

Reading: MEDICAL MICROBIOLOGY by P.R. Murray, K.S. Rosenthal, and M.A. Pfaller, 6th Edition. pp. 835-839.

OVERVIEW

Malaria is a febrile disease that causes anemia. It was once endemic in the U.S. and is currently one of the most common infections worldwide, infecting 300–500 million people annually. For map of worldwide distribution click "here".

Etiology

Malaria is caused by obligate intracellular protozoan parasites of the genus "Plasmodium". The four species of human malarial parasites are Plasmodium vivax, P falciparum, P malariae, and P ovale.

Manifestations

The incubation period for malaria is around 7-30 day. There is a brief prodromal period with symptoms of fever, headache, and myalgia. Symptoms begin with a cold stage (a shaking chill), following by a fever stage (40–41°C) that lasts about 24 hours, and finally a wet stage. The wet stage occurs several hours after the fever, when the body temperature drops quickly to normal and profuse sweating begins. The patient is exhausted but well until the next cycle of fever begins. Other symptoms include splenomegaly and anemia.

Three basic types of malaria

1. Benign tertian (P vivax and P ovale) with a fever every 2nd day (e.g., Monday; fever, Tuesday; no fever, Wednesday; fever).

2. Benign quartan (P malariae) with a fever every 3rd day (e.g., Monday; fever, Tuesday; no fever, Wednesday; no fever, Thursday; fever).

3. Malignant tertian (P falciparum), in which the cold stage is less pronounced and the fever stage is more prolonged and intensified (if the fever is recurring it occurs every 2nd day). However, the fever is usually continuous or only briefly remittent. There is no wet stage. This type of malaria is more dangerous because of the complications caused by capillary blockage (i.e., convulsion, coma, acute pulmonary insufficiency, and cardiac failure). Large numbers of erythrocytes are parasitized and destroyed, which may result in dark-colored urine (blackwater fever; intravascular hemolysis, hemoglobinuria, and kidney failure.).

Two species of Plasmodium, P vivax and P ovale, can remain in the liver, if not treated properly. The organisms leave the liver and re-infect erythrocytes, causing the symptoms described above. Relapsing malaria occurs when there are relapses many years after the initial episode of malarial disease.

Epidemiology

Each year 350-500 million cases of malaria occur "worldwide". About 1 million people die of malaria each year; 75% of deaths are African children.
The highest transmission rates are found in countries in sub-Saharan Africa.
About 41% of the world’s population lives in areas where malaria is transmitted (e.g., parts of Africa, Asia, the Middle East, Central and South America, Hispaniola, and Oceania).
P vivax is the most common cause of malaria and is found in subtropical and temperate areas of the world. P vivax and P ovale cause relapsing malaria.
P falciparum is found in tropical regions and causes the most severe and fatal disease.
P malariae is limited entirely to subtropical areas. The species is less common than P falciparum or P vivax.
P ovale is the least common malarial species and is endemic in Africa.
Although malaria is no longer endemic in the U.S., about 1200 cases of malaria are reported each year.
Malaria is transmitted primarily by the bite of an infected Anopheles mosquito.
Most cases of malaria in the U.S. occur after travel to countries that have endemic malaria. P falciparum is the most common species of malarial parasite diagnosed in the U.S., followed by P vivax, P malariae, and then P ovale.

Pathogenesis

The general features of the following parasitic life cycle apply to all Plasmodium species. Sporozoites are the infective form, transmitted during the blood-meal feeding of a female Anopheles mosquito on a human. The sporozoites invade and reside within hepatocytes, where they increase. Several days after the initial infection, some of the sporozoite progeny (called merozoites) leave the liver and enter the bloodstream to infect erythrocytes and form the trophozoite, or ring-cell stage of the parasite. Individuals who do not express the erythrocyte Duffy antigen are resistant to P vivax infections.

The erythrocyte stage begins when merozoites infect the red blood cells. The parasites attach to specific red blood cell receptors and are endocytosed to initiate infection. The Duffy blood group protein is the red blood cell receptor that P vivax uses to bind to the surface of erythrocytes. An individual who is negative for the Duffy antigen (FyFy rather than Fya or Fyb) is resistant to infection by P vivax. Asexual reproduction (schizogony) proceeds through a series of stages resulting in the rupture of the erythrocyte and the release of up to 25 merozoites per erythrocyte.

Fever is the hallmark symptom of malaria and is induced when the erythrocytes rupture and merozoites are released. Vasodilation and hypotension occur in response to the high fever. Anemia results following erythrocyte destruction and indirectly from increased phagocytosis of red cells, capillary hemorrhage, thrombosis, and decreased marrow function. The most severe anemia is associated with P falciparum infection. A brown to black pigmentation of organs occurs when the malarial pigment hemozoin is ingested by phagocytes in lymphoid tissue, liver, spleen, and bone marrow. Hemozoin is a partially digested form of human hemoglobin produced in the digestive food vacuole of the parasite while it dwells in the erythrocyte.

Hepatomegaly and splenomegaly occur following dilation of the sinuses and are due to the increased numbers of macrophages in these organs, especially the spleen. Parasitized red blood cells in immune complexes occlude capillaries and cause local hemorrhaging and anoxia in many tissues, with the brain being the most severely affected. In severe disease, intravascular hemolysis in the kidney can cause hemoglobinemia and hemoglobinuria and dark colored urine called blackwater fever. After the immune response has terminated the erythrocytic cycle, P vivax and P ovale hypnozoites can remain dormant in the liver and cause relapse months to years later.

After one or more asexual cycles in the erythrocytes, some intraerythrocytic merozoites develop into male and female gametocytes, which are the sexual forms of the parasite. Gametocytes are ingested by the mosquito and can fuse within the mosquito’s gut to form a zygote, which initiates the sexual reproductive cycle (sporogony). After several developmental stages in the mosquito, the parasite migrates to the salivary glands of the mosquito as a sporozoite.

Diagnosis

Diagnosis of malaria is obtained following visualization of parasitized erythrocytes in thick or thin peripheral blood smears stained with Wright or Giemsa stain (ring-cell stage). Serology includes agar diffusion, passive hemagglutination, immunofluorescence, and an ELISA. Malaria-specific antibody is not detectable until after symptoms begin and is useful for patients who have negative blood smears and for detecting carriers of P vivax and P ovale in blood used for transfusions. This recurring febrile disease can be confused with other recurring febrile illnesses (e.g., brucellosis and relapsing fever). Table E-1 lists the differences in the length of the fever and fever periodicity.

Table E-1. Some Diseases with Recurring Fevers: Causative Agent, Periodicity of Fever, and Length of Fever
Disease	Causative Agent	Periodicity of Fever	Length of Fever
Malaria	Plasmodium	Every 2–3 days (except P falciparum where fever can be continuous)	Fever lasts 24 hours, with the fever ending in a drenching sweat
Brucellosis	Brucella	Every day	Fever recurs in the evening and is gone by morning, ending in a drenching sweat
Relapsing fever	Borrelia	Every 7–10 days	Fever lasts 7–10 days

Therapy and Prevention

Once the diagnosis of malaria has been confirmed, appropriate antimalarial treatment must be initiated immediately (Table E-2). Malarial infections can be prevented using mosquito control measures and insecticide-treated mosquito netting. Chemoprophylaxis includes taking chloroquine when in chloroquine-sensitive areas. In areas with chloroquine-resistant P falciparum, quinine sulfate, mefloquine, or atovaquone/proguanil is suggested. Because these chemoprophylaxis agents do not eliminate P vivax and P ovale (forms of the parasite that remain in the liver), primaquine phosphate treatment is recommended when living in endemic areas.

*Table E-2. Treatment of Plasmodium* Infections Listed by Species and Chloroquine Resistance**
Species	Chloroquine Resistance	Therapy
P falciparum	No	Chloroquine
P falciparum	Yes	Quinine sulfate plus doxycycline, tetracycline, or clindamycin OR atovaquone-proguanil OR mefloquine
P vivax	No	Chloroquine plus primaquine phosphate*
P vivax	Yes	Quinine sulfate plus doxycycline or tetracycline plus primaquine phosphate* OR Mefloquine plus primaquine phosphate*
P malariae	No	Chloroquine
P ovale	No	Chloroquine plus primaquine phosphate*

*The other drugs used to treat malaria only eliminate the parasites in the erythrocytes. P vivax and P ovale produce hypnozoites that dwell in the liver. Relapses of malaria will be more likely to occur if primaquine phosphate, a drug that eliminates the liver forms (hypnozoites) of the parasite, is not used in treating patients with these diseases from these Plasmodium species.

A good place for advice on prevention is the "CDC".