OVERVIEW: What every clinician needs to know

Malaria continues to be the most important tropical disease affecting humans. The condition is caused by protozoa of the genus Plasmodium. Infection is transmitted to humans by the female anopheline mosquito.

The genus Plasmodium includes > 170 different species that infect mammals, reptiles, birds, and amphibians. Four species have long been known to cause malaria in humans: Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. More recently, P. knowlesi, which normally infects long-tailed and pig-tailed macaque monkeys, has been implicated as a cause of human malaria in South East Asia—Borneo, Thailand, Singapore, and parts of the Philippines.

Despite the eradication of endemic malaria from the developed parts of North America and Europe, it is estimated that the disease occurs in approximately 600 million people worldwide and causes an estimated one to three million deaths each year, where the majority are in patients five years or younger. The disease is caused by one of the five different Plasmodium species (see above), but the majority of the morbidity and mortality attributed to malaria, especially central nervous system (CNS) involvement, are caused by P. falciparum. With the exception of the Caribbean and parts of Central America, P. falciparum strains are usually resistant to chloroquine.

Malaria sporozoites are transmitted from the saliva of the female Anopheles mosquito to the patient when the mosquito bites a person for its blood meal. Within 8 hours, thousands of sporozoites are carried rapidly to the liver where they multiply asexually in approximately seven to ten days to become liver (tissue) schizonts (also known as pre-erythrocytic schizonts) or the dormant hypnozoites produced by P. vivax and P. ovale. These pre-erythrocytic liver schizonts contain tens of thousands of merozoites. When they mature, these schizonts cause the infected hepatocyte to burst, releasing thousands of merozoites into the bloodstream. The merozoites attach to surface receptors on the erythrocytes, then penetrate and infect individual erythrocytes, residing in a vacuole that is lined with material from the surface of the red cell itself. The merozoite transforms to the trophozoite in the vacuole, feeding on hemoglobin of the host red blood cell. The early trophozoite manifests as the classic ring forms seen on light microscopy. The trophozoite enlarges in the vacuole and grows to occupy most of the erythrocyte, and after about 24 – 36 hours enters a second stage of asexual division to form an erythrocytic schizont, each containing 12 – 24 merozoites per infected erythrocyte. This schizogony occurs in the blood for malaria caused by P. vivax, P. ovale, and P. malaria; usually in P. falciparum malaria schizogony occurs only in deep capillaries.

The receptors necessary for attachment are specific for the Plasmodium species. For example, P. vivax attaches to the red blood cell via a receptor related to the Duffy blood-group antigen. Thus, individuals from west Africa, who generally have Duffy-negative blood, are resistant to invasion and infection by P. vivax. Even now, P. vivax infection remains uncommon among indigenous western Africans.

What is the best treatment?

1. Before any course of action is decided, it is recommended that the clinician should call the CDC malaria hotline at 1-770-488-7788 or 1-855-856-4713 (8am-5pm Eastern Time) and if after hours, 770-488-7100. This is a standard recommendation for all clinicians who encounter a patient with malaria and are unsure of the diagnosis and or the treatment plan. If uncomplicated P. falciparum malaria is diagnosed, or if malaria is suspected but infective species is not known, or if the infection is mixed, initial treatment should be as if the patient had P. falciparum malaria with quinine, or atovaquone/proguanil (Malarone), or artemether/lumefantrine (Coartem.) Because of widespread resistance throughout Africa, Southeast Asia, and Latin America, the World Health Organization recommends using artesunate combination therapy, where available, for treatment of all P. falciparum malaria. Coartem contains 20 mg of artemether and 120 mg of lumefantrine.

Quinine used for the treatment of P. falciparum malaria: 600 mg quinine P.O. every 8 hours for 5-7 days in conjunction with either doxycycline 200 mg daily for 5-7 days or clindamycin 450 mg every 8 hours for 7 days. Quinine is well absorbed after oral or intramuscular administration. If the parasite is likely to be sensitive, pyrimethamine with sulfadoxine (Fansidar) as a single-dose (75 mg pyrimethamine and 1.5 g sulfadoxine) may be given instead of doxycycline or clindamycin.
Artemether/lumefantrane (Coartem) may be given instead of quinine. The dose is four tablets twice daily orally for three days (i.e., 24 tablets over 60 hours).
Atovaquone/proguanil (Malarone) is considered the safest of all antimalarials and may be given instead of quinine. This combination is effective against chloroquine-resistant P. falciparum malaria and acts by preventing development of the parasites in the liver.
Note: Fansidar is an adjunct to treatment with quinine and is not recommended for prophylaxis. Also, pyrimethamine is not recommended alone; it is usually given with sulfadoxine. The toxicity of Fansidar is generally related to the sulfa component rather than the pyrimethamine.
Note: It is not necessary to prescribe doxycycline, clindamycin, or Fansidar after Malarone or Artemether-lumefantrane treatment.

2. Severe P. falciparum malaria. Again, prior to any course of action being initiated, it is recommended that the clinician should call the CDC malaria hotline at 1-770-488-7788 or 1-855-856-4713 (8am-5pm Eastern Time) and if after hours, 770-488-7100. This is a standard recommendation for all clinicians who encounter a patient with malaria and are unsure of the diagnosis and or the treatment plan. If patient is seriously ill, or unable to take oral therapy, parenteral antimalarial therapy is indicated. Intravenous artesunate should be used in preference to quinine for severe falciparum malaria in adults. Also, artesunate administration does not depend on rate-controlled infusion or cardiac monitoring.

Treatment with artesunate is 2.4 mg/kg stat IV on admission, then at 12 hours and 24 hours, then once daily.
If parenteral artesunate is not available, then quinine should be given by intravenous infusion. The loading dose of quinine is 20 mg/kg up to a maximum of 1.4 g of quinine salt infused over 4 hours, then 8 hours after the start of the loading dose a maintenance dose of 10 mg/kg (up to a maximum of 700 mg) of quinine salt infused over 4 hours every 8 hours until patient can swallow tablets to complete the 7-day course of therapy followed by either doxycycline or clindamycin as described above.
Quinidine is considered more toxic than quinine because of its association with hypotension and QT prolongation. It is used if no other parenteral drug is available but only with electrocardiogram monitoring and regular assessment of vital signs.
Exchange transfusion for severe malaria is no longer recommended and in fact could potentially worsen the course of the patient.

3. If benign malaria (caused by P. vivax, and less commonly by P. ovale, P. malariae, and P. knowlesi) is diagnosed, chloroquine is the drug of choice for treatment. The initial dose is 620 mg of base followed by a single dose of 310 mg of base after 6 – 8 hours then 310 mg of base daily for 2 days. Chloroquine alone is satisfactory for treatment of P. malariae infection. However, in the case of benign malaria caused by P. vivax or P. ovale, elimination of parasites in the liver is indicated and is achieved by administration of oral primaquine: for P. vivax infection, the primaquine dose is 30 mg daily for 14 days; for P. ovale infection the dose 15 mg daily for 14 days.

Before starting primaquine, the patient should be tested for glucose-6-phosphate dehydrogenase (G6PD) activity since primaquine can cause hemolysis in persons with G6PD deficiency. For mild G6PD deficiency in adults, primaquine is given at a dose of 45 mg once weekly for a total of 8 weeks (for children, 750 micrograms once a week for 8 weeks).
If the patient is unable to take any kind of oral medication, quinidine is given by intravenous infusion.

Pathogenesis

P. falciparum is the cause of the most malignant form of malaria and is associated with almost all serious complications associated with the infection. Cerebral malaria, in particular, is the most prominent and serious of these complications. Attributable mortality remains relatively high (20%) and is often associated with delays in diagnosis and treatment. As P. falciparum trophozoites mature in the red blood cells, they induce the formation of small protein knobs on the surface of the erythrocyte. These knobs appear on the surface of the erythrocyte about 15 hours after penetrating and invading the cell, and then bind to adhesion proteins, also known as intercellular adhesion molecule-1 (ICAM-1), on the microvascular endothelial cells lining capillaries in various organs and tissues in the body. The resulting cytoadherence of parasitized erythrocytes to the endothelial cells leads to sequestration of large numbers of these cells in deep tissues. Sequestration is the process whereby erythrocytes containing mature forms of P. falciparum adhere to microvascular endothelial cells, resulting in marked reduction or disappearance of these cells from the circulation. ICAM-1 is important for sequestration in the brain. Sequestration does not occur in malaria caused by P. vivax, P. ovale, or P. malariae.

Sequestration of erythrocytes in small blood vessels and consequent obstruction of microcirculatory flow is a specific property of P. falciparum and an important mechanism causing coma and death in cerebral malaria. The second important factor in the pathogenesis of cerebral malaria is the increase in chemokines/cytokine production. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response in which cells of the macrophage-monocyte lineage are induced to release various chemokines/cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-8. However, this response may also induce complications, such as severe anemia, hypoglycemia and cerebral malaria.

The adhesion molecules are up-regulated in malaria as a result of cytokine productions, TNF-α in particular. Furthermore, parasitized erythrocytes tend to adhere to adjacent uninfected cells leading to rosetting. In addition, as the parasite matures inside the erythrocyte, the normally flexible cell becomes more spherical and rigid. Because of the rosetting and increased rigidity of parasitized erythrocytes, the erythrocytes become trapped in the capillaries. The end result of cytoadherence, rosetting and rigidity is the enhancement of sequestration of P.
falciparum-parasitized erythrocytes in the cerebral vasculature, stagnation of the cerebral blood flow, and secondary ischemia leading to tissue hypoxia, lactic acidosis, hypoglycemia, and prevention of delivery of nutrients to the tissues. High concentrations of TNF-α can precipitate cerebral malaria by increasing the sequestration of parasitized erythrocytes. Although all tissues potentially can become involved including cardiac muscle and gastrointestinal system, the brain is the most profoundly affected.

In the CNS, this process results in delirium, impaired consciousness, convulsions, paralysis, coma, and ultimately, rapid death if not treated. Systemic manifestations of severe falciparum malaria include anemia, lactic acidosis, hypoglycemia, pulmonary edema, adult respiratory distress syndrome, and disseminated intravascular coagulation. Of note, the pathophysiology of malaria does not include vasculitis or inflammatory cellular infiltration in or around the cerebral vasculature, and most patients have no evidence of cerebral edema. Raised intracranial pressure likely arises from an increase in the overall cerebral blood volume rather than brain swelling arising from cerebral edema and capillary leakage. Coma in malaria is generally not associated with raised intracranial pressure. Clinical features of P. falciparum malaria include fever and chills (83%), altered sensorium (48%), jaundice (27%), anemia (75%), cerebral involvement (45%), thrombocytopenia (41%), and renal failure (25%).

The diagnosis should be considered in a person with altered consciousness, fever, and a relevant travel history, which is critically important to elicit as is the history of whether the patient took or was compliant with prophylaxis for malaria. The location of the travel is particularly critical as P. falciparum is typically resistant to chloroquine. Resistance to trimethoprim-sulfamethoxazole, mefloquine, and other agents have been documented in many parts of the world, particularly Southeast Asia and Sub-Saharan Africa. Because there is no latent form of P. falciparum in the liver, as there is for P. vivax and P. ovale, cases of P. falciparum malaria should become clinically evident within a month after leaving an endemic area.

The gold standard laboratory diagnosis for malaria is made from examination of the blood smear. Although delay is common because of the time needed for their preparation and reading, thick and thin blood smears remain the cornerstone of laboratory diagnosis of malaria in current practice. Despite the availability of rapid diagnostic testing for the detection of malaria based on lateral-flow immunochromatography, in which clinicians can detect malaria parasite antigens from finger-prick blood specimens within 10 – 15 minutes, microscopic examination of blood smears remains the most cost-effective methodology for diagnosis of malaria, provided the results reach those who need to know in a timely manner. This is why in many parts of the world, this is still the mainstay of diagnosis.

Rapid diagnostic testing (RDT) kits based on molecular platforms with high sensitivity and high negative predictive value for P. falciparum would be of particular use in acute care settings in regions of low malaria endemicity, where the diagnosis is suspected but lack of laboratory expertise precludes the diagnosis and reading of blood smears. Lastly, rapid diagnostic testing may benefit severely ill patients by confirming or excluding a malaria diagnosis rapidly and facilitating prompt intervention. Rapid test kits for malaria have limitations that preclude replacing microscopy of blood smears any time soon. These limitations include the inability to ascertain parasitemia quantitatively or to differentiate between the four Plasmodium species.

Treatment of cerebral malaria

Untreated cerebral malaria is fatal. In cases of severe malaria with CNS involvement, the patient must be treated as though they have P. falciparum malaria regardless of the preliminary interpretation of the blood smear. According to the CDC, if severe malaria is strongly suspected but a laboratory diagnosis cannot be made at that time, blood should be collected for diagnostic testing as soon as it is available and parenteral antimalarial drugs started empirically. After discussion with the clinicians at the CDC malaria hotline [at 1-770-488-7788 or 1-855-856-4713 (8am-5pm Eastern Time) and if after hours, 770-488-7100], a course of action will be initiated. Once the diagnosis is considered likely, parenteral quinidine gluconate should be started. The recommended therapeutic regimen includes a loading dose of 6.25 mg base/kg (=10 mg salt/kg) infused intravenously over 1 – 2 hours, followed by a continuous infusion of 0.0125 mg base/kg/min (=0.02 mg salt/kg/min). Parental artemisinin is the preferred treatment (due to reduced complications) and can be released by the CDC malaria hotline clinician, and then transported by airplane to the clinical location of the patient. Most patients diagnosed with a 5% parasitemia will clear the parasites from the blood stream within approximately 24h period.

An alternative regimen is an intravenous loading dose of 15 mg base/kg (=24 mg salt/kg) of quinidine gluconate infused intravenously over 4 hours, followed by 7.5 mg base/kg (=12 mg/kg salt) infused over 4 hours every 8 hours, starting 8 hours after the loading dose. Quinidine gluconate therapy should be combined with doxycycline, tetracycline or clindamycin. If the patient is unable to tolerate oral therapy, doxycycline (100 mg every 12 hours) or clindamycin (5 mg base/kg every 8 hours) may be given intravenously until the patient can be switched to oral therapy.

Parenteral quinidine gluconate is cardiotoxic and can induce hyperinsulinemic hypoglycemia. Thus, a baseline electrocardiogram should be obtained before initiating therapy and glucose levels must be monitored closely. Critical care management includes continuous cardiac and blood pressure monitoring with appropriate supportive management of coexisting medical complications often associated with severe malaria: convulsions, renal failure, adult respiratory distress syndrome, disseminated intravascular coagulation, lactic acidosis, hypoglycemia, fluid and electrolyte abnormalities, circulatory collapse, acute renal failure, secondary bacterial infections, and severe anemia.

Intravenous corticosteroids are associated with poor outcomes and are absolutely contraindicated in the management of cerebral malaria. Brain swelling on CT scan is a common finding in adult patients with cerebral malaria but is not related to coma depth or survival. Mannitol therapy as adjunctive treatment for brain swelling in adult cerebral malaria prolongs coma duration and may be harmful. Results of studies of antipyretics, anticonvulsants (phenobarbitone), anticytokine/anti-inflammatory agents (anti-TNF antibodies, pentoxifylline, dexamethasone), iron chelators, and hyperimmune sera have not proven beneficial in improving patient outcomes.

With treatment, almost all patients with CNS malaria recover completely if they survive the acute episode. However, globally, overall mortality in children and adults remains unacceptably high. Approximately 12% of patients with cerebral malaria may have lasting neurologic sequelae, including cortical blindness, tremor, cranial nerve palsies, and sensory and motor deficits, although approximately 50% of these sequelae resolve with time.

What are the clinical manifestations of infection with this organism?

Key symptoms

Uncomplicated malaria: symptoms are many and include fever, rigors, headache, malaise, anorexia, diarrhea, and cough. Symptoms are associated with the blood stage rather than the liver stage.
Severe malaria due to P. falciparum may develop in patients who initially presented with relatively mild symptoms and low parasitemia. This underscores the importance of making the diagnosis of P. falciparum malaria quickly.
The classical states of fever seen in a paroxysm of malaria are most often recognized in malaria caused by P. vivax infection.

Cold stage – the patient shivers or has a frank rigor and temperature rises sharply.

Hot stage – the patient is flushed, and has a full rapid pulse and sustained pyrexia

Sweating stage – there is sweating with drenching of clothes and bed linen. The temperature falls rapidly.

The typical periodicity of these paroxysms in the classic textbooks and papers is 48 hours for P. falciparum, P. vivax, and P. ovale; 72 hours for P. malariae;and 24 hours for P. knowlesi. However, these patterns of fever paroxysms are frequently not observed or documented in the clinical setting, especially in non-immune individuals, and therefore should not be used as the basis for making or ruling out a diagnosis of malaria.

Complicated malaria: patients with P. falciparum malaria may present with symptoms of acute renal failure with or without oliguria or hemoglobinuria, pulmonary edema and respiratory distress syndrome, disseminated intravascular coagulation (DIC), vomiting and diarrhea, intravascular hemolysis jaundice and fever, shock, severe anemia, delirium, disorientation, stupor, coma, convulsions, or focal neurological signs.
The median incubation period of P. falciparum malaria is about 12 days and maximum presentation would be at day 28. Compared with the other types, onset is often insidious. Patients can present with flu-like symptoms such as fever, headache, malaise, aches and pains, and jaundice resulting in an initial diagnosis of infectious mononucleosis or viral hepatitis. The fever is irregular and generally does not follow a tertiary pattern.
The incubation period of P. vivax malaria is on average 13 – 17 days. Onset is abrupt with chills and rigors, usually around noon or early afternoon. This “cold stage” lasts about an hour and is usually followed by a “hot stage” which lasts 4 – 6 hours, during which the patient develops high fever, headache, malaise, vomiting, abdominal pain, thirst, and polyuria. The “hot stage” is followed by the “sweating stage”, which lasts about one hour during which the fever defervesces and the symptoms resolve.

Key physical findings

Fever, drenching sweats, herpes labialis, splenomegaly, jaundice. Anemia is common.
Algid malaria: acute shock syndrome associated with vascular collapse may be the presenting feature of P. falciparum malaria. Gram-negative bacteremia is a well-recognized feature of this syndrome.
Tropical splenomegaly syndrome is well recognized in hyperendemic areas. It is uncommon before the age of 10. Key clinical features include splenomegaly and elevated IgM levels, and IgM aggregates in the Kupffer cells of the liver.
Cerebral malaria: children are particularly affected. Acute encephalopathy associated with convulsions, drowsiness, stupor and coma. Patients may manifest signs consistent with an upper motor neuron lesion, extensor posturing, and disconjugate gaze. On fundoscopy, papilloedema or retinal hemorrhages might be present.
Acute renal failure may be the presenting clinical feature with oliguria, prerenal uremia or complete anuria. This is an uncommon complication in children. Hemoglobinuria may be present in patients with renal failure with few demonstrable parasites in blood smears. This condition, otherwise known as Blackwater fever, is uncommon but is well described in patients with malaria and glucose-6-phosphate dehydrogenase deficiency. Precipitating factors include treatment with primaquine and various sulpha-containing agents.
Hypoglycemia: this complication is most frequent in African children and is due to glycogen depletion, not treatment with quinine.
Tissue anoxia: this complication may be caused by sequestration of parasitized erythrocytes, resulting in impaired tissue perfusion; anemia; hypovolemia; or hypotension.

Malaria in pregnancy

Pregnancy is associated with an increased likelihood of acquiring Plasmodium parasitemia. Moreover, malaria infection in pregnancy is a significant cause of anemia, abortion, or babies with low birth weight, particularly first-pregnancy babies. Malaria in pregnancy leads to accumulation of parasitized erythrocytes in the placental microcirculation. Congenital infection may occur in malaria caused by all species; the usual syndrome is a progressive hemolytic anemia in a child who is failing to thrive.

Congenital malaria is more common with P. vivax malaria.

Do other diseases mimic its manifestations?

Dengue
Typhoid fever
Viral hemorrhagic fevers
Pneumonia
Influenza
Gastroenteritis
Viral hepatitis
Leptospirosis
Amoebiasis
Salmonella septicemia
Rickettsial infections
Meningococcal meningitis
Viral encephalitis

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Complete blood count often shows mild normochromic normocytic anemia, thrombocytopenia, and leukopenia.
Erythrocyte sedimentation rate and C-reactive protein (CRP) levels are generally elevated.
Biochemistry: potassium is usually normal although mild hyponatremia may be present. Severe metabolic acidosis may result in a widened anion gap
Liver enzyme tests may show elevated levels of bilirubin, alanine transaminase (ALT) and aspartate transaminase (AST). Blood glucose levels may be low.
Cerebrospinal fluid is usually normal in cerebral malaria although concentration of protein may be elevated. The lactate concentration is raised in proportion to disease severity. The CSF may appear yellow if the patient is deeply jaundiced.

Results that confirm the diagnosis

Thick and thin blood smears remain the gold standard for diagnosis in endemic countries. Smears can be stained with Giemsa, Wright, or Leishman stains. In a patient with suspected malaria, two to three blood smears taken each day for 3 – 4 days and deemed to be negative for parasite forms are necessary before malaria can be ruled out. See Table I.

Table I.

Characteristic blood smear findings seen in infection with different Plasmodium species

	Early	Late
P. falciparum	Not enlarged; Maurer’s clefts; multiple in a single red blood cell	6-12 merozoites; daisyhead form of schizonts
P. vivax	Enlarged; Schuffner’s dots	12-24 merozoites
P. ovale	Enlarged; fimbriated ends	6-12 merozoites
P. malariae	Not enlarged; Ziemann’s dots	6-12 merozoites

Although delay is common because of the time needed for formal thick and thin blood smear preparation and reading, thick and thin blood smears remain the cornerstone of laboratory diagnosis of malaria in current practice. In regions of the world with low endemicity, malaria rapid diagnostic testing (RDT) with high sensitivity and predictive value negative for P.
falciparumis particularly useful, especially in regions of low endemicity where the diagnosis is suspected but laboratory expertise in malaria diagnosis is not available. Malaria RDT may benefit severely ill patients by confirming or excluding a malaria diagnosis rapidly, and facilitating prompt intervention where indicated. Limitations of RDT include their relatively high costs and inability to quantify parasitemia. Polymerase chain reaction (PCR) testing is highly sensitive and specific albeit time-consuming and expensive. Serodiagnosis is of no use for the diagnosis of an acute attack of malaria. The main use of serodiagnosis is in excluding malaria in persons with a history of recurrent bouts of fever who are not seen during an actual bout.
The most important aspect in the clinical diagnosis of malaria is to have a high index of suspicion and obtain a comprehensive travel history.

What imaging studies will be helpful in making or excluding the diagnosis of Plasmodium species?

Chest radiographs are indicated if a patient with suspected malaria presents or develops pulmonary circulatory collapse with cough, hemoptysis and features of acute lung injury.

What complications can be associated with this parasitic infection, and are there additional treatments that can help to alleviate these complications?

Cerebral malaria
Algid malaria: characterized by severe vomiting, diarrhea and circulatory collapse. The pulse is rapid and of poor volume, and arterial hypotension is profound. Patients may present with this feature, or it may be the first manifestation of Gram-negative septicemia.
Tropical splenomegaly syndrome: characterized by massive splenomegaly and lymphocytic infiltration of hepatic sinusoids. It is thought to be due to an abnormal immunological response to repeated malarial infection, and is one of the most common causes of massive splenomegaly in sub-Saharan Africa and Papua New Guinea. Malaria parasites are rarely found. Serum IgM levels and malarial antibody titers are elevated. Patients respond to extended courses of treatment with Proguanil (200 mg daily).
ARDS (idiopathic pulmonary edema): pulmonary edema in pregnancy is often associated with severe acidosis and renal failure. Careful monitoring of intravenous rehydration is of paramount importance.
Shock lung
Hepatorenal syndrome
Spontaneous splenic rupture
Hypoglycemia
Nephrotic syndrome: associated with malaria caused by P. malariae
Acidosis

What is the life cycle of the parasite, and how does the life cycle explain infection in humans?

There are two life cycles: that in humans and the other in the parasites. Humans are the intermediate hosts. Sporozoites, the infective form of the parasite, are injected into the bloodstream of a human when the Anopheles mosquito is taking its blood meal, initiating the start of the human cycle. Sporozoites in the bloodstream are removed by the body’s defense systems; however, those not eliminated develop into liver schizonts. After a number of days, the liver schizont ruptures and merozoites are liberated into the bloodstream. For P. vivax and P.ovale, the sprozoites may develop into hypnozoites – a latent form that remains in the liver.
Once in the bloodstream, the merozoites infect red blood cells, where they go through several stages of trophozoite development before developing into erythrocytic schizonts. These parasitic forms are asexual. The erythrocytic schizonts finally rupture releasing merozoites into the circulation. The median time from initial inoculation of sporozoites to release of merozoites varies by Plasmodium species: 9 days for P. falciparum and 12 days for P. vivax.
Approximately 0.5-2% of the merozoites develop into haploid sexual forms known as gametocytes; only mature gametocytes are found in the peripheral blood. The patient is infective during this stage. The sexual cycle in the mosquito commences when the Anopheles mosquito ingests a blood meal containing gametocytes.
The Anopheles mosquito is the definitive host; humans remain intermediate hosts. Seasonal variation has been documented in Sub-Saharan Africa.
P. ovale is predominant in in East and West Africa. P.
vivaxis widespread throughout the tropical and sub-tropical areas of the world.
Malaria remains a major cause of morbidity and mortality in tropical and sub-tropical countries.

Infection control issues: there are no reasons for isolation precautions for patients who have malaria specifically.
Prophylaxis

Prophylaxis against malaria is generally indicated for persons who travel to endemic regions. The factors that need to be taken into consideration before deciding on a drug for an individual who requires prophylaxis include the following:

(i) The intrinsic factors associated with the person—e.g., age, sex, kidney and liver function, history of idiosyncratic reactions to certain drugs; pregnancy.

(ii) The prevalence of malaria in the region to be visited.

(iii) The potential risk of exposure to bites of mosquitoes that transmit malaria.

(iv) The efficacy and side effects of recommended drugs.

(v) The prevalence of drug resistance. It is best to access the websites of the Centers for Disease Control and Prevention or the World Health Organization to ascertain the relative risk of acquiring malaria in the country or region to be visited.

Generally, prophylaxis should be started from 3 days to one week (2 – 3 weeks in the case of mefloquine) before date of travel to an endemic region. The key reasons for the pre-travel commencement of prophylaxis are to establish tolerance to the respective drug and to ensure an adequate plasma level of the agent by the time the person arrives at the destination.

Malarone or doxycycline prophylaxis should be started 2 days before travel. Doxycycline should be continued for 4 weeks after leaving the malarial region; Malarone should be stopped one week after leaving.

Specialist advice should be sought for long-term prophylaxis. The agents commonly used for long-term prophylaxis include proguanil, mefloquine, doxycycline, and Malarone.

For persons with a history of epilepsy, chloroquine and mefloquine are unsuitable for prophylaxis. Instead, doxycycline or Malarone should be considered.

In patients with renal impairment, Malarone or proguanil should not be used. Mefloquine and doxycycline are appropriate for prophylaxis in patients with renal impairment.

Pregnant women, generally, should avoid travel to malaria-endemic countries. If travel is unavoidable, chloroquine and proguanil can be given in the usual doses. Doxycycline and Malarone are contraindicated.

Prophylaxis should be considered in breast-fed infants since the amount of the agent present is the milk is variable and unpredictable.

Because asplenic patients are at particular risk of acquiring malaria, prophylaxis should be considered for this patient population.

Is vaccination recommended?

An effective vaccine is not as yet available for routine use in the prevention of malaria. Yet, clinical trials are being conducted currently using various merozoite-erythrocyte stage surface proteins, and then challenging subjects with that species of Plasmodium.
Are there strategies for avoiding exposure to the vector?

For the visitor to an endemic region, the first step of prevention is instituting protection against mosquito bites. That means personal protection against bites through the use of permethrin-impregnated bed-nets and mats at the entry of houses; use of insect repellents such as > 25% diethyltoluamide (DEET) applied to the skin; and use of long sleeves and trousers worn after dark and for pajamas (Anopheles mosquitoes are night biters, especially late night). In addition, the washing or spraying clothing with permetherin has been shown to be effective in repelling mosquitos as well and is used as a compliment to integumental DEET application.
Are there ways to eliminate the vector or interrupt its life cycle?

Malaria control is a complex endeavor that entails several broad components:

(i) Management of water level.

(ii) Modification of human behavior.

(iii) Activities against the adult mosquito.

(iv) Larval control using larvicide agents.
Water level management involves drainage of standing water or other potential breeding sites that facilitate mosquito egg-laying and larval development. Other environmental engineering include changing the salinity or pH of an aquatic body or allowing organic matter pollution (mosquitoes prefer clean rather than polluted water for the laying of eggs). Such alterations of the environment may lead to long-term problems for wild-life, not to mention public health.

Modifications of human behavior that facilitate malaria control include the wearing of sensible clothing at dusk and at bedtime; use of insect repellents and malaria-proof bed-nets that are impregnated with insect repellents or insecticides. Finally, containers, such as water barrels or tanks should be covered, and clean-up of environmental pollution with bottles or plastic containers should be a priority.

Activities against the adult mosquito (imagocidal) involve the use of agents that kill or deter adult mosquitoes. These agents include pyrethrins, chlorinated hydrocarbons (e.g., DDT dieldrin), and anticholinesterases. Unfortunately, the adult mosquito vector has responded to these agents by changing their feeding and resting preferences. Strains of mosquitoes resistant to the insecticides have evolved.

Larval control involves the use of various chemical agents, larvivorous fish, and bacterial toxins with activity against larvae. Organophosphate compounds have been used with limited success.

How does this organism cause disease?

What key virulence factors allow the pathogen to colonize, spread from person to person, invade tissue and cause tissue destruction?

Continued asexual replication in the bloodstream through repeated cycles of maturation and rupture of red cells with release of merozoites results in symptomatic infection. Several virulence factors play key roles in the pathogenesis of disease that eventually affect vital organs, blood flow in the microvasculature, and host metabolism in various tissues, including the brain, lungs, kidneys, heart, adipose tissues, and skin. The key virulence factors that lead to tissue destruction include the following:

(i) Strain-specific parasite-derived proteins that facilitate cytoadherence leading to sequestration.
(ii) Elements that foster rosetting of erythrocytes (rosetting is similar to cytoadherence in some respects, but tend to result in more severe obstruction of the microvasculature than cytoadherence).
(iii) Toxicity cytokines (e.g., TNF) which are responsible for many of the symptoms and signs of infection (chemokines/cytokines are elevated in both P. falciparum and P. vivax malaria).
(iv) Intrinsic parasite factors that affect the deformability of the parasitized red blood cell.
(v) Immunologic factors that are associated with the formation of immune complexes, antigen-specific unresponsiveness, and interference with the orderly development of a specific immune response.
(vi) Factors that lead to an increase in systemic vascular permeability.

How do these virulence factors explain the clinical manifestations?

As P. falciparum trophozoites mature in the red blood cells, they induce the formation of small knobs on the surface of the red cell. These knobs bind to adhesion molecules (also known as intercellular adhesion molecule-1) on the microvascular endothelial cells, leading to sequestration. Sequestration is the process whereby erythrocytes containing mature forms of P. falciparum adhere to microvascular endothelial cells, resulting in marked reduction or disappearance of these cells from the circulation. Sequestration of erythrocytes in small blood vessels and consequent obstruction of microcirculatory flow is a specific property of P. falciparum and an important mechanism causing coma and death in cerebral malaria. Sequestration occurs predominantly in the venules of vital organs.

An important factor in the pathogenesis of cerebral malaria is the increase in cytokine production. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response in which cells of the macrophage-monocyte series are induced to release various cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-8. However, this response may also induce complications, such as severe anemia, hypoglycemia and cerebral malaria. Cytokines promote cytoadherence and although they mediate parasite killing by activating leukocytes, the resulting oxygen species and peroxides are harmful to the patient.

Parasitized erythrocytes tend to adhere to adjacent uninfected cells leading to rosetting. In addition, as the parasite matures inside the erythrocyte, the normally flexible cell becomes more spherical and rigid. Because of the rosetting and increased rigidity of parasitized erythrocytes, the erythrocytes become trapped in the capillaries. The end result of cytoadherence, rosetting and rigidity is the enhancement of sequestration of P.
falciparum-parasitized erythrocytes in the cerebral vasculature, stagnation of the cerebral blood flow, and secondary ischemia leading to tissue hypoxia, lactic acidosis, hypoglycemia, and prevention of delivery of nutrients to the tissues. In the CNS, this process results in delirium, impaired consciousness, convulsions, paralysis, coma, and ultimately, rapid death if not treated. Systemic manifestations of severe falciparum malaria include anemia, lactic acidosis, hypoglycemia, pulmonary edema, adult respiratory distress syndrome, and disseminated intravascular coagulation.

The pathophysiology of malaria does not include vasculitis or inflammatory cellular infiltration in or around the cerebral vasculature, and most patients have no evidence of cerebral edema.

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Plasmodium species (Malaria)