Infectious Diseases

Plasmodium species (Malaria)

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, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. More recently, a fifth, Plasmodium 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 the Philippines.

Despite its eradication from North America and Europe, it is estimated that malaria infects over 2.5 billion people worldwide and causes between one and three million deaths each year. The disease is caused by one of the five different Plasmodium species (see above), but the majority of the deaths and serious complications of malaria, especially central nervous system (CNS) involvement, are caused by P. falciparum.

P. falciparum malaria, also known as malignant malaria, is caused by P. falciparum and is responsible for most of the deaths due to malaria. In most parts of the world, P. falciparum is resistant to chloroquine. Benign malaria is caused by P. vivax, P. ovale, and P. malariae and is usually amenable to treatment with 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 schizonts contain tens of thousands of merozoites. When they mature, these schizonts cause the infected liver cells to burst, releasing thousands of merozoites into the bloodstream. The merozoites attach to the red blood cells by means of surface receptors, then penetrate and infect red blood cells, 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. 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, West Africans, who generally have Duffy-negative blood, are resistant to invasion and infection by P. vivax. Even now, P. vivax infection remains uncommon among indigenous Africans.

The time interval between mosquito bite and entry of merozoites into the bloodstream is about 10 - 14 (range: 7 - 28) days and is known as the prepatent period. Continued asexual replication in the bloodstream through repeated cycles of maturation and rupture of red cells with release of merozoites eventually results in symptomatic infection. During this process, a fraction of the merozoites undergo sexual differentiation and develop into sexual forms called gametocytes, which produce no symptoms themselves but which may circulate for a prolonged period of time. It is the ingestion of male and female gametocytes that leads to the sexual reproduction cycle in the female Anopheles mosquito, resulting in the motile sporozoites which form a zygote in the mosquito midgut. The zygote then matures to an ookinete, which penetrates and encysts in the lining of the mosquito intestinal wall. The resulting oocysts enlarge, then rupture to release sporozoites that then invade the mosquito salivary glands to complete the life cycle. These sporozoites are then transmitted back to humans at the time of the next blood feed.

In P. vivax and P. ovale infections some of the hepatic stage parasites do not divide immediately but remain in a dormant form or hypnozoite. The period of dormancy may range from weeks to over one year before replication resumes. This period of dormancy and delayed replication underscore the tendency for relapse that is characteristic of P. vivax and P. ovale infections.

Malaria is widely distributed in economically less-developed countries, particularly Sub-Saharan Africa, Central America and the Caribbean, South America, the Middle East, Far East, and Indonesia. P. falciparum infection is predominant in Africa, New Guinea and some parts of the Caribbean, especially Haiti and the Dominican Republic. P. falciparum and P. vivax are encountered in South America and the Indian subcontinent. P. malariae is found most commonly in sub-Saharan Africa but may be encountered in most endemic areas. P. knowles infection has been found in Borneo and South East Asia.

The epidemiology of malaria is determined by a complex interplay of multiple factors, including mosquito vector density, ambient temperatures and other environmental conditions, population movements, altitude, parasitemia rates among endemic populations, and the longevity of the anopheline mosquito. The reader is strongly urged to access the CDC's website for the most up-to-date data on the epidemiology, geographic distribution, and drug resistance among Plasmodium spp. on a country by country basis.

P. vivax and P. ovale generally infect young erythrocytes, while P. malariae has a predilection for old cells. For this reason, these three species seldom manifest a parasitemia >2%. In contrast, P. falciparum infects erythrocytes of all ages and can therefore manifest with parasitemia levels often >5%.

Relapse, recurrence, and recrudescence are three important complications of Plasmodium infections that must be appreciated and understood in the context of untreated malaria. For malaria caused by the two relapsing malaria—P. vivax and P. ovale—treatment with a blood schizonticide invariably results in an immediate response. Relapse is due to resumption of replication of previously dormant hypnozoites in the liver with development into pre-erythrocytic schizonts that produce merozoites that reinvade the bloodstream. Relapse is usually prevented by treating with a course of primaquine. Following a single exposure/mosquito bite, the infected person may die during the acute attack or develop humoral and cellular immunity, and attacks may recur over the ensuing year. A recurrence may be either a recrudescence or reinfection. A recurrence is called a recrudescence if it is caused by the persistence of blood forms in small numbers between attacks. Recrudescences may occur over a period of many years. Recurrence is defined as reinfection if it is due to a new inoculation of sporozoites from a mosquito vector.

What is the best treatment?

1. 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 for P. falciparum malaria with quinine, proguanil with Atovaquone (Malarone), or artemether with 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 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 salt every 8 hours for 5 - 7 days followed by 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 with 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).

  • Proguanil with atovaquone (Malarone) is considered the safest of all antimalarials and may be given instead of quinine. This combination is effective against chloroquine-resistant 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 sulpha 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. 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.

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 knobs on the surface of the red cell. 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 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.

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, 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 laboratory diagnosis of 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.

Rapid diagnostic testing 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 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. 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).

An alternative regimen is an intravenous loading dose of 15mg base/kg (=24mg 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. More recently, artemisinin derivatives such as parenteral artesunate have been shown to substantially reduce mortality in African children with severe malaria; the authors go on to suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.

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 incubation period of P. falciparum malaria is about 12 days and seldom more than 28 days. 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 bacteremia

  • 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. falciparum is 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 shock lungs.

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 micromerozoites 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 micromerozoites 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 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.

  • A few of the merozoites develop into 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

  • 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 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.

  • 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 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.)

  • 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 (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.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

"Centers for Disease Control and Prevention: Guidelines for Treatment of Malaria in the United States (Based on drugs currently available for use in the United States – updated September 23, 2011)". http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf.

"Centers for Disease Control and Prevention: Treatment of malaria (guidelines for clinicians)". http://www.cdc.gov/malaria/diagnosis_treatment/.

"World malaria report 2014. 1. Malaria - prevention and control. 2. Malaria - economics. 3.Malaria - epidemiology. 4.National Health Programs - utilization. 5.Insecticide-Treated Bed Nets. 6.Antimalarials - Therapeutic Use. 7.Drug Resistance. 8.Disease Vectors. 9.Malaria Vaccines. 10. Annual Reports. I. World Health Organization".

"World Health Organization: Malaria case management operations manual. 1. Malaria - epidemiology. 2. Malaria - prevention and control. 3. Malaria - drug therapy. 4. Malaria - diagnosis. 5. Case management - administration and organization. 6. Antimalarials. 7. Health services. 8. Health profile. 9. Manual. I. World Health Organization. II. Global Malaria Programme". http://www.who.int/malaria/publications/atoz/malaria_case_management_operations_manual.pdf.

"WHO Library Cataloguing-in-Publication Data Guidelines for the treatment of malaria -- 2nd edition. 1. Malaria – drug therapy. 2. Malaria – diagnosis. 3. Antimalarials – administration and dosage. 4 Drug therapy, Combination. 5. Guidelines. I World Health Organization".

Lalloo, DG, Shingadia, D, Pasvol, G, Chiodini, PL, Whitty, CJ, Beeching, NJ, Hill, DR, Warrell, DA, Bannister, BA. "HPA Advisory Committee on Malaria Prevention in UK Travellers. UK malaria treatment guidelines". J Infect. vol. 54. 2007. pp. 111-21.

"Committee to Advise on Tropical Medicine and Travel: Canadian recommendations for the prevention and treatment of malaria among international travellers". CCDR. vol. 35. 2009. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/09vol35/35s1/index-eng.php.

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/337761/Guidelines_for_malaria_prevention_in_travellers_UK_PC.pdf.

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