2.1.1 Overview
Malaria is an acute flu-like parasitic illness that affects humans at any age. The disease is caused by one of the four species of the genus Plasmodium (P.), P.
falciparum, P. vivax, P. ovale, or P. malariae, respectively. The protozoon is transmitted by infected female mosquitoes of the genus Anopheles when it settles on a person to take a blood meal. The disease is characterized by recurrent periods of chills and fever. Infection with P. falciparum can be fatal, whereas infection with P.
vivax and P. ovale does not result in death; however, these strains have the ability to remain dormant in the liver for many months and can delay the occurrence of clinical signs of malaria for several months after the initial infection. Relapses of malaria infection may also occur with these strains. The incidence of P. malariae infection is patchy. This variant causes malaria with paroxysms recurring every fourth day, so called quartan malaria, due to schizogony and invasion of new red blood cells by parasites (ANONYMUS, 2005; McADAM and SHARPE, 2005).
At first, it was thought that malaria originated in marshes and swamps and was transmitted through the air. According to the Italian expression "mal" and "aria" - meaning "bad air" - the term “malaria” was applied to this disease. The real cause was discovered on 6th November 1880, when Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, noticed parasites in the blood of a patient suffering from malaria. Subsequently it was discovered that malaria is caused by a single cell parasite, which was called “Plasmodium” (RAMHARTER and WINKLER, 2005).
2.1.2 Geographic distribution of malaria and its incidence
Malaria is endemic in most tropical and sub-tropical countries of sub-Saharan Africa, in large areas of the Middle East, South Asia, South East Asia, Oceania, Haiti, Central and South America and in parts of Mexico, North Africa and the Dominican Republic (Fig. 2.1). It represents one of the largest scourges in third world countries, affecting approximately 300 - 500 million people, and killing three million people
annually. In endemic areas, the number of malaria cases increases from time to time dramatically to an epidemic level (ANONYMUS, 2003; McADAM and SHARPE, 2005;
RAMHARTER and WINKLER, 2005). The population of Africa suffers the most from malaria, and it is reported that 90% of malaria cases are diagnosed in Africa, mainly among young children and pregnant women. It is reported that malaria causes the death of an African child every 30 seconds (ANONYMUS, 2003).
Fig. 2.1 Geographic distribution of malaria (CENTERS FOR DISEASE CONTROL AND PREVENTION http://www.dpd.cdc.gov)
2.1.3 Risk factors
All human beings are at risk to acquire malaria. However, this tropical infection is more severe particularly in the following individuals:
Children up to an age of 5 years
Adults over 65 years old
Pregnant women
People treated with steroids or those receiving chemotherapy
Patients with acquired HIV infection (Aids patients)
Splenectomized people
People suffering from porphyry, epilepsy or chronic illness (BECK et al., 1994).
2.1.4 Clinical disease and complications
Infected people may show one or more of the following clinical signs:
1. Periods of chills and sweats 2. High fever
3. Anorexia
4. Orthostatic hypotension characterized by low blood pressure causing dizziness when moving from a lying or sitting to a standing position
5. Muscle aches 6. Headache 7. Abdominal pain
8. Diarrhea, nausea, and vomiting
In untreated cases of P. falciparum infection additional signs may develop including:
Infection of the brain (cerebral malaria) with or without seizures and confusion resulting in coma and death
Renal failure
Abnormal and compromised liver function
Anemia
Pulmonary edema
Leukopenia
Hypoglycemia
Lactic acidosis
Hyponatremia
Hematuria indicating hemolysis due to parasitic destruction (so called Black water fever) (ANONYMUS, 2005).
Correct and rapid diagnosis of malaria infection is required, and treatment can be successful with a variety of drugs.
2.1.5 Life cycle and transmission of the Plasmodium parasite
When a mosquito bites a person infected with malaria, it ingests male and female individuals of the parasite (gametocytes). The gametocytes unite in the stomach of the mosquito forming an oocyst. The oocyst takes about a week to mature followed by sporogony in the midgut. Subsequently the sporocyst ruptures releasing thousands of sporozoites, which migrate through the hemocoel to invade the salivary
glands of the mosquito. When this mosquito bites a human, sporozoites are injected into the bloodstream. The sporozoites reach rapidly the liver and infect hepatocytes.
They develop within 6 – 8 days into schizonts, which rupture and release merozoites into the blood stream. In some cases of P. vivax or P. ovale infection, the merozoites can remain inactive in the liver for extended periods of time. Later, reactivation of the parasite's life cycle causes a relapse.
Upon maturation, merozoites in the blood invade erythrocytes, followed by development of trophozoites, which can infect erythrocytes again or generate gametocytes. The latter can be ingested by a mosquito and perpetuates the developmental cycle.
With the burst of one infected erythrocyte, plenty of parasites are released ready for infection of numerous red blood cells. With each wave of hemolysis - about every 48 to 72 hours (Fig. 2.2), depending on the Plasmodium species - the person suffers from periods of chill, fever and sweating. Typically, signs start between 10 - 28 days after the initial mosquito bite, although they can appear as early as eight days or as late as one year after infection (BLOLAND and WILLIAMS, 2003).
In many cases, treatment or the immune response eliminates the parasite.
Particularly in children, who have yet to acquire immunity against the parasite, complications of the infection may lead to death. In addition, P. falciparum is capable of invading a much greater number of red blood cells than the other species of Plasmodium, and the infection can be fatal within a few hours after initial hemolysis (CENTERS for DISEASE CONTROL and PREVENTION http://www.dpd.cdc.gov/DPDx/). In pregnant women, the infection may be transmitted transplacentarly to the fetus. In addition, malaria has been transmitted via blood transfusion using infected donor blood samples (DUFFY and DESOWITZ, 2001).
2.1.6 Treatment and drug resistance
A malaria infection, particularly with P. falciparum, requires prompt diagnosis and treatment. In most cases, malaria can be effectively treated with one or more of the following drugs:
Chloroquine
Quinine sulfate
Hydroxychloroquine
Fig. 2.2 Schema of the Life Cycle of Malaria
The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . (Of note, in P. vivax and P.
ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are responsible for the clinical manifestations of the disease.
The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites’ multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes)
which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the mosquito's salivary glands.
Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle . (CENTERS FOR DISEASE CONTROL AND PREVENTION http://www.dpd.cdc.gov)
Combination of sulfadoxine and pyrimethamine
Mefloquine
Combination of atovaquone and proguanil
Doxycycline
Oocyst Release of
sporozoites
Mosquitotakes a blood meal (injects Sporozoites)
Because of the relentless increase in resistance of malaria parasites to conventional drugs, new therapeutic approaches have been developed, among them the artemisinin-based-combination therapy (ACT) is most important (SULLIVAN and KRISHNA, 2005).