Malaria

Practice Essentials

Malaria is an ancient and continuously unmatched parasitic cause of human suffering throughout the world. Plasmodium spp, an obligate intracellular protozoon using the mosquito as its vector, permeates the tropical and subtropical world. Historically, it has crushed societies, devastated militaries, and hampered economic growth.^{[1, 3]} It continues to wreak havoc, targeting and killing the most vulnerable in our global society.

The most common human-infecting Plasmodium species are P falciparum, P vivax, P malariae, and P ovale, with P falciparum being the most dangerous. In addition, the zoonotic species P knowlesi, primarily infecting non-human primates, increasingly is affecting humans in forested regions of certain countries in Southeast Asia and the Western Pacific.^{[1, 2, 3]}

Signs and Symptoms^{[2, 3]}

• Malaria may range from mild to severe disease complicated by profound end-organ damage.
• Typically beginning with a flu-like illness, the hallmark symptom of malaria is its paroxysmal fever that can last up to 10 hours at a time. The classic description is a quartan (every 72 hours) or tertian (every 48 hours) fever periodicity synchronized with Plasmodium merozoites bursting from red blood cells during malaria’s asexual erythrocytic phase. These paroxysms occur with abrupt cold “chills” that transitions after about an hour to profuse sweating, high fever, headache, malaise, and myalgias – then subsequent defervescence.
• Infection with malaria can result in several physiologic derangements such as anemia, acidosis, and hypoglycemia to name a few. Due to its tendency to transition to an adherent phenotype, infection with P falciparum predisposes patients to thrombosis and thrombocytopenia throughout the body.
• Cerebral malaria is characterized by its variable presentation of neurologic decline, often leading to coma and convulsions.

Diagnosis^{[2, 3]}

• The gold-standard diagnostic test for malaria remains direct visualization of the parasite by an experienced microscopist from thick & thin blood smears.
• Rapid tests that evaluate for the presence of malarial antigens in the blood are available but may have lower sensitivities and depending on the region and genetics of the prevalent species; they cannot differentiate species accurately.
• Polymerase chain reaction (PCR) also is available at reference laboratories for molecular species-level identification.

Management^{[2, 3]}

• The treatment of malaria depends on clinical severity, local medical resources, geography, local Plasmodiumspp. prevalence, patient genetics, historical use of malaria chemoprophylaxis by the patient, knowledge of local anti-malarial drug resistance, and the patient’s pregnancy status.
• Most treatment regimens for Plasmodium falciparum, the deadliest species, involve artemisinin combination therapy.
• Clinically severe disease requires intravenous therapy with eventual step-down to completion of an oral regimen.
• Patients with P vivax or ovale infections require anti-relapse therapy with an 8-aminoquinolone (primaquine or tafenoquine) after initial treatment; this is due to the species’ abilities to form hypnozoites in the liver, which are untouched by the typical schizontocides used for acute treatment. 

• References

Background

In 2022 the World Health Organization’s “World Malaria Report” indicated that between 2000-2019, deaths per year from the parasitic disease had declined from 897,000 to 568,000, with overall cases declining from 245 million to 232 million. Concurrent with the COVID-19 pandemic, malaria’s death toll and case count unfortunately increased to 619,000 and 247 million in 2021, respectively – 76% of whom were children and 52% of whom occurred in just 4 countries: Nigeria, the Democratic Republic of Congo, the Republic of Niger, and the United Republic of Tanzania.^[1]  The present-day devastation caused by malaria sadly is nothing new to the world.

History

Implications on civilization include the following:

• Malaria has affected the development of human civilization for millennia.^[4]  Likely accounts of the disease have been found in most developed ancient societies such as Mesopotamia, India, China, Egypt, Greece, and Rome; these accounts have been covered extensively by both modern popular and scientific writings.^[5]  Malaria even has been postulated to have protected against invaders while simultaneously accelerating the demise of ancient Rome via its presence in the Pontine Marshes. The presence of Plasmodium falciparum on the Apennine peninsula may have led to the many reports of outbreaks of deadly fevers between the 1^st and 2^nd centuries AD.^[6]
• The efficient Anopheles mosquito vector enabled malaria to suppress economic productivity and development in the subtropical regions around the globe, especially within sub-Saharan Africa. Plasmodium falciparum’s deadly course repelled European traders for centuries and was powerful and persistent enough to potentially select for different genetic profiles such as “sickle-cell trait” in African natives.^[4]
• At the turn of the 20^th century, Colonel William Gorgas and the United States military led the charge in malaria prevention, proving efficacy of environmental vector control for the Panama Canal Commission. Through swamp drainage, oil spraying, employing “mosquito swatters,” installing screens in living quarters, and instituting the use of anti-malarial prophylaxis with quinine, malaria case incidence was reduced from 800 per 1,000 workers to 16 per 1,000 in a matter of 3 years.^[7]  Malaria eventually was eradicated from the United States in 1951, yet the Anopheles vector persists.^[8]  Granting that treatment advanced over the first half of the century, malaria has continued to wreak havoc on a global scale. It exposed itself in the Second World War as the US Navy and Marine Corps alone suffered over 100,000 cases and 3.3 million “sick-days” due to malaria.^[9]  Most intensely, in the South Pacific on the island of Guadalcanal there was an astonishing case incidence of 1,781 per 1,000 per year in November 1942 amongst US and Allied forces. Lower incidence rates and case numbers occurred in the Korean and Vietnam conflicts; however, malaria remains a major issue for forward deployed forces globally, with many modern cases requiring telemedicine consultation from infectious disease specialists in the states.^[10]

Discovery

The following were significant in the discovery of malaria:

• In 1880, while stationed in Algeria, the French Army physician Charles Louis Alphonse Laveran discovered the protozoal cause of malaria using a microscope with dry objective at 400x magnification.^[11]  As this discovery refuted the miasma theory as well as the leading germ theory of the time that espoused a bacterial cause of the disease, it took the better part of a decade to convince other leading researchers in the field that a protozoa was the pathogenic agent. In 1907, Laveran received the Nobel prize in medicine for his discoveries.
• Using the English Army physician Ronald Ross’ work with avian malaria as a foundation, a series of Italian physician scientists - notably Giovanni Grassi, Amico Bignami, and Giuseppe Bastianelli incriminated the Anopheles mosquito as the vector for human malaria and further elucidated the protozoan’s life cycle.

• References

Etiology

There are four common Plasmodium species that primarily affect humans, with a fifth species in Southeast Asia, known as Plasmodium knowlesi, which can rarely infect humans and lead to severe disease. However, this species generally infects monkeys. The majority of malaria cases worldwide are caused by P falciparum, followed by P vivax.^[1]  

Biology

Figure 1. Malaria life cycle

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Malaria life cycle. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

Stages of Infection ^[12]

Infection

• Infection occurs during the mosquito’s blood meal as the female Anopheles inserts her proboscis into human skin and injects up to 100 sporozoites (sporo- meaning “spores,” -zoite meaning “animal”) per bite with her saliva, each of them gliding at speeds up to 2 micrometers per second. After waiting 1 to 3 hours in the dermis, the successful sporozoites reach the bloodstream and are swiftly carried off through the blood to the liver, where they must cross the sinusoidal barrier to access and invade their target hepatocytes. 

Exoerythrocytic Schizogeny – “Liver Stage”

• Once they have transitioned from migratory to invasive phenotypes, the sporozoites mature into spherical multinuclear schizonts (schiz- meaning “divided,” -ont meaning “type”). After 5-21 days depending on species, each liver schizont ruptures into 2,000 to 40,000 uninucleate merozoites (mero- meaning “part,” -zoite meaning “animal”).

Erythrocytic Schizogeny - “Blood Stage”

• At this point, each merozoite may infect a red blood cell; differences between the species at specific stages are noted below. The parasites begin to feed off hemoglobin within the erythrocytes, with the parasites first appearing as ring forms, then forming trophozoites (tropho- meaning “nourishment,” -zoite meaning “animal”). Hemozoin is the brown pigment biocrystal waste product generated from the parasite’s hemoglobin meal; this results in safe disposal of the free-radical-generating heme molecule that otherwise would be toxic to the Plasmodium. Trophozoites again mature into schizonts, which rupture into merozoites, thus continuing the erythrocytic or “blood” stage. Some trophozoites mature into sexual stage gametocytes rather than schizonts. These male and female gametocytes then may be ingested by another feeding Anophelese mosquito. 

Sporogony - “Mosquito Stage”

• Male and female gametocytes ingested by a mosquito undergo sexual reproduction in the gut of the mosquito, producing motile ookinetes (oo- meaning “egg,” -kinete meaning “relating to motion”), which invade the wall of the mosquito midgut, forming oocysts. The oocysts subsequently rupture, releasing sporozoites that invade their way to the mosquito’s salivary glands and await a new human host.^[12]

Species Specific Nuances

P falciparum

• ​Typical incubation period: 8-11 days^[13]
• Classic fever periodicity: 36-48 hours
• • A main feature of P falciparum is its ability to convert to its cytoadherent phenotype by insertion of P falciparum erythrocyte membrane protein 1 (pfEMP1) into the membrane of erythrocytes, which leads to the negative effects of infected erythrocyte sequestration.^[15]  Sequestration of infected erythrocytes can throw off the accuracy of microscopy determined parasitemia. pfEMP1 is the product of var gene transcription, of which there are ~60 copies, making it a highly variable antigen that also contributes to immune evasion.

   

  

   

P vivax

• Typical incubation period: 8-17 days (but may be 1 year or more due to hypnozoite formation)^{[13, 16]}
• Classic fever periodicity: 48 hours
• • Both P vivax and P ovale are known to variably enter quiescence after hepatocyte invasion. These hypnozoites (hypno- meaning “sleeping”) result in primary infection weeks to months (up to 1 year or more) about 50% of the time.^[17]  This serves as a mechanism for relapsed infection despite treatment of the patient with schizonticidal agents; when P vivax or P ovale are suspected pathogens, the affected patient must receive presumptive anti-relapse therapy (PART) with primaquine or tafenoquine to target the hypnozoites. Other antimalarials are ineffective against hypnozoites, but if the patient is unable to receive PART, chloroquine prophylaxis should be provided for 1 year from the acute infection, as most of the relapses resulting from hypnozoite reactivation occur within this timeframe.^[2]
  • P vivax infects reticulocytes preferentially via the Duffy antigen present on red blood cells.^{[18, 19]}  Incidentally, most Africans are Duffy-negative, and there is a low prevalence of P vivax on that continent. Ethiopia, India, Indonesia, and Pakistan account for more than 75% of all cases.

   

  

   

P ovale

• Typical incubation period: 10-17 days (but may be 1 year or more due to hypnozoite formation)^{[13, 20]}
• Classic fever periodicity: 48 hours
• • Like P vivax, P ovale also produces hypnozoites in the hepatic phase of its life cycle (see above).
  • P ovale typically produces a milder infection compared to P falciparum or P vivax and may self-resolve after 6-10 paroxysms, but it does cause significant morbidity in endemic areas (ie, West Africa).^{[13, 21]}

   

  

   

P malariae

• Typical incubation period: 18-40 days^[22]
• Classic fever periodicity: 72 hours
• • P malariae infections typically cause lower parasitemia and account for a minority of the malaria burden in the world.^[21]  P malariae infection also is associated with proteinuria and membranoproliferative glomerulonephritis secondary to immune complex deposition.^[13]  Because of the slow maturation process as indicated by the long incubation period, low parasitemia infections may persist for long periods of time with recrudescence up to 50 years. 

   

  

   

​P knowlesi

• Typical incubation period: 9-12 days ^[13]
• Classic fever periodicity: 24-27 hours
• • P knowlesi is a simian malaria that has been found to cross into humans in Southeast Asia – particularly on the island of Borneo.^[1]  It resembles P falciparum in early erythrocytic stages and as it matures it resembles P malariae on microscopy; this unfortunately puts the patient at risk of being diagnosed with a less severe infection. In contrast to P malariae, P knowlesi infections progress to severe disease at a high rate (~8%); therefore, if a patient is diagnosed with high parasitemia malaria identified as P malariae by microscopy, it should be assumed that the patient has a severe P knowlesi infection until proven otherwise.^[12]

   

  

   

• References

Epidemiology

The WHO reports that, as of 2021, malaria was endemic in 85 countries, placing nearly half the world’s population at risk of contracting the disease.^[1]  Modern US travelers acquire almost 90% of malaria by traveling to Africa; almost 9% of the disease is acquired in Asia, whereas South and Central America/ the Caribbean make up the remainder.^[23]  In these patients, there is a 14% risk for severe disease, and 13% of the cases initially are misdiagnosed.

Epidemiologic measures ^{[18, 24]}

• Entomologic inoculation rate: sporozoite-positive mosquito bites per unit time
• Annual parasite incidence: number of new parasite-confirmed cases per 1000 population
• Spleen rate: proportion of individuals of a given age with enlarged spleens

Transmission ^{[18, 24]}

• The female Anopheles mosquito requires the protein from a blood meal to produce its eggs. This genus serves as the vector for human malaria; there are more than 400 species of Anopheles. However, only 40 species of Anopheles transmit malaria to humans.^[3]  Varying amongst species-specific preferences, the mosquitos lay their eggs in water ranging from large open bodies such as ponds to much smaller collections like puddles from footprints. The eggs hatch into larvae, then molt several times to become pupal stages of adults. When protein for egg production is required, the adult female is attracted to many chemical indicators of human activity: CO₂, lactic acid, odors, and moisture. Typically, they feed at night or in the late evening or early morning, and after feeding, the mosquitos display different preferences in where and how long they rest before biting again. All these differences in species-specific preferences are of importance when it comes to vector control.
• • High transmission: >450 cases per 1,000 people annually and P falciparum prevalence >35%
  • Moderate transmission: 250-450 cases per 1,000 people annually and P falciparum/ vivax prevalence 10-35%
  • Low transmission: 100-250 cases per 1,000 people annually and P falciparum/ vivax prevalence 1-10%
  • Very low transmission: < 100 cases per 1,000 people annually and P falciparum/ vivax prevalence 0-1%

   

  

   
• Epidemiology of clinical cases is affected by the background of acquired protective immunity to the parasite. In areas with continuously moderate to high transmission, repeated exposure to the parasite reduces the risk of adolescents and adults contracting severe disease. If environmental control measures effectively limit transmission in a given area, the population’s acquired immunity decreases over time; this necessitates sustainment of the transmission-control efforts to prevent a subsequent increased risk for epidemic severe malaria. The same premise applies to previously immune people who have traveled away from the endemic for an extended period of time (ie, 1 year or more).

Geography of modern disease burden ^{[1, 24]}   

• Several geographic traits influence transmission levels and burden of disease: altitude, humidity, annual rainfall, proximity to bodies of water, land use, and temperature.

The maps below were generated using data obtained from the WHO 2022 World Malaria Report.

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Proportion of 2021 Global Malaria Burden. Gray area accounts for the remaining estimated 4.4% of worldwide malaria burden. Map created using data adap....

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Confirmed P falciparum or P vivax Cases Per Country 2021. The map accounts for the total of the cases per country where either species were confirmed ....

North America

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North American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Ma....

South America

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South American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Ma....

Europe

Per the WHO 2023 World Malaria Report, no 2022 case data exists for the European region. Malaria was eradicated from Europe in the 1970s through insecticide spraying, drug therapy, and environmental engineering; however, climatic conditions are becoming more conducive to malaria transmission and the large influx of migrant populations may serve as an adequate parasite reservoir.^{[1, 25]}

Africa

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African Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map creat....

Asia & South Pacific

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Asian and Oceanic Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases.....

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South Pacific Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map....

Species-Specific Epidemiology

P falciparum and vivax are the most common species of malaria that cause disease in humans – see the map below for proportional comparison of the cases caused by the 2 species from 2021.^{[1, 24]}

• Americas – P vivax (76%), P falciparum & mixed (24%)
• Eastern Mediterranean – P vivax (24%), P falciparum & mixed (74%), other (2%)
• South-East Asia – P vivax (44%), P falciparum & mixed (55%), other (1%)
• Western Pacific – P vivax (32%), P falciparum & mixed (68%)
• High transmission countries in East & Southern Africa – P vivax (< 1%), P falciparum (>99%)
• Low transmission countries in East & Southern Africa – P vivax (8%), P falciparum & mixed (92%)
• Central Africa – P falciparum (100%)
• West Africa – P falciparum (>99%), other (< 1%)
• P vivax infects reticulocytes preferentially via the Duffy antigen present on red blood cells.^{[18, 19]}  Incidentally, most Africans are Duffy-negative, and there is a low prevalence of P vivax on that continent. Note that Ethiopia, India, Indonesia, and Pakistan account for more than 75% of all P vivax cases. As previously mentioned, P ovale is endemic to West Africa, and P knowlesi has been identified in South-East Asia. P malariae is found throughout the tropics; however, most cases seen in US travelers are mixed infections in returning travelers from Africa. ^[21]  The percentage of cases attributed to P vivax decreased from approximately 8% (20.5 million) in 2000 to 3% (6.9 million) in 2022.^[1]

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Global P falciparum to P vivax Case Ratios 2021. Gray indicates that there were either no data available or there were zero endemic cases. Red indicat....

• References

Prognosis

Most patients with uncomplicated malaria exhibit marked improvement within 48 hours after the initiation of treatment and are fever free after 96 hours. P falciparum infection carries a poor prognosis with a high mortality rate if untreated. However, if the infection is diagnosed early and treated appropriately, the prognosis is excellent.^[3]

Mortality

In 2021, 247 million malaria cases occurred globally with 619,000 deaths, 96% of which occurred in the African region.^[3]  Roughly 80% of the deaths occurred in children younger than 5 years. Although preventable and treatable, poverty, war, and economic/ social instability in endemic areas historically have resulted in close to 1 million deaths each year.

Population Protective & Risk Factors

Genetic variation and population dynamics play a prominent role in the global patterns of malaria prognosis and epidemiology.

Age-Related

• The peak age of uncomplicated malaria declines as transmission intensity declines – however, the youngest age groups (specifically those younger than 5 years) are at most risk for hospitalization and death despite the epidemiology of transmission. Furthermore, the peak age of death caused by malaria is in children younger than 1 year. This has led to age-targeted mitigation strategies such as intermittent preventive treatment of infants and children as well as vaccine development.^[26]
• As peak age also declines with increasing severity of disease, it suggests that immunity develops against more severe forms of malaria more swiftly than immune protection against clinical disease. This singularity may be exaggerated by the tendency for those unable to mount strong immune responses to die from malaria at an earlier age.^{[3, 26]}

Sex-Related

• Recent public health data from Uganda indicate that females in the 15-39 age group are more likely to be at risk for suspected malaria compared to other demographics. While males in the same age range and older have higher test positivity rates, females in the study had nearly double the incidence of malaria. Additionally, females were more than twice as likely as males to seek healthcare at local facilities for recent fever symptoms. Furthermore, females also had a higher frequency of non-malaria-related healthcare visits compared to males.
• Previous studies have reported a male bias in incidence and prevalence of malaria infection, and another study out of Uganda showed that this was potentially secondary to females clearing asymptomatic infections at a faster rate than males.^[27]  This has lent strong evidence to the theory that males are less able to control parasite densities (anti-parasite immunity), leading to higher male prevalence of infection, whereas females are less able to tolerate higher parasite densities without fever (anti-disease immunity), leading to a higher likelihood of experiencing symptoms.^[26]  This evidence suggests the presence of sex differences regarding acquisition of immunity to malaria.^[3]

Genetics-Related

• • Starting with the association of HbS (sickle cell trait) and less severe disease and less parasitemia discovered by AC Allison published in 1954, several different polymorphisms in the hemoglobin genes have been linked to protection against severe malaria.^[28]  This is especially true in geographic regions of Africa where malaria transmission is higher.^[29]  Apart from HbS, case control studies have shown that alpha and beta-thalassemia as well as HbC disease are protective against malaria – all 3 conferring greater than 50% protection against severe forms of malaria.^[30]  The mechanisms of protection differ amongst the hemoglobinopathies and likely are multifactorial; reduced erythrocyte invasion and maturation, reduced development of adherent phenotypes, and increased erythrocyte clearance in response to oxidative stress all may be contributory mechanisms. 

   

  

   
• • Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme required for NADPH production and subsequent glutathione reduction to protect red blood cell membranes against oxidative damage. A deficiency of G6PD is the most common inherited red blood cell abnormality, affecting over 400 million people, with up to 30% of them residing in sub-Saharan Africa.^[29]  It is X-linked (more so affecting males), and homozygosity of the deficiency can lead to severe episodes of hemolysis. Despite its potential downside, it has been shown to be highly protective against severe malaria via increased splenic phagocytosis of ring-form infected erythrocytes.^[31]  The prevalence of the protective polymorphisms of G6PD deficiency also are associated with malaria transmission intensity in endemic countries.

   

  

   
• • Apart from P vivax requiring the Duffy antigen for erythrocyte entry, the risk conferred by other blood groups has been elucidated.^[19]  The rosetting phenomenon, which occurs through the cytoadherent phenotype of P falciparum-infected erythrocytes clumping and clogging of microvessels, is much less likely to occur in patients with group O RBCs. This is because A and B antigens serve as rosetting receptors for uninfected RBCs. This leads to a much lower likelihood of severe malaria in patients with group O blood; a study in Mali showed an odds reduction for severe versus uncomplicated malaria in group O patients of 66%.^[32]

   

  

   

• References

Pathophysiology

Malaria Pathogenesis

Despite the many morphologies of the parasite in its life cycle, only a few stages cause clinical disease in humans, the most severe of which are typically P falciparum and P vivax.^[15]  The initial schizont broods rupture out of the liver phase, release thousands of merozoites into the bloodstream, and attempt to establish periodicity within the erythrocytic phase (time periods vary per species) where level of parasitemia increases exponentially.

• • Once the parasite concentration is high enough, a fever is mounted (pyrogenic threshold). This pyrogenic threshold may be anywhere from 0.05 to 1.25 parasites/1,000 red blood cells (0.005 - 0.125% parasitemia) – immune patients may require 0.2% parasitemia to experience fever.^{[13, 33]}  The most theorized mechanism for the cyclic fevers is the human immune response to the hemozoin (waste product generated from Plasmodium’s diet of hemoglobin) that bursts into the bloodstream during each cycle of asexual erythrocytic schizogony.^[34]  Hemozoin is known to be a Plasmodium pathogen associated molecular pattern (PAMP) recognized by toll-like receptors (TLRs) that induces intense immune response. Other malarial toxins such as malaria glycophosphatidylinositol (GPI) likely are culpable through similar mechanisms. The temperature fluctuation with the human febrile response is expected to play a role in guiding the broods of parasites toward the classic paroxysmal fever-associated periodicity of schizont rupture.

   

  

   
• • Severe malaria-associated anemia typically is seen in the young in areas of the world with poor health infrastructure and diets poor in essential vitamins.^[35]  Schizont rupture from erythrocytes is an obvious mechanism of anemia; however, the more profound loss of red blood cell mass is seen in the population of uninfected erythrocytes. Their decline is thought to occur via oxidative damage of the erythrocyte membranes, eventually leading to hemolysis. Another mechanism of anemia lies within bone marrow; both insufficient production and function of erythropoietin as well as possible apoptosis induction of erythrocyte precursors lead to dyserythropoiesis.

   

  

   
• • During acute malaria infection, the spleen serves as the main driver of infected erythrocyte clearance, immune cell activation, and extramedullary hematopoiesis.^[36]  The extraordinary burden on the spleen causes the red pulp to become congested with infected and uninfected red blood cells, but splenomegaly also occurs by massive cellular expansion in both the red and white pulp. Impressively, the organ is able to revert back to a normal size after clearance of the infection (at least in mice). Because of P vivax’ tropism for reticulocytes (prevalent in the spleen), splenic rupture is a characteristic severe complication of P vivax, and there is evidence to suggest a separate splenic life cycle for this species.^[37]

   

  

   
• • End-organ damage from microvascular sequestration, respiratory depression, and production of Plasmodium lactate dehydrogenase (pLDH) by the malaria parasite all lower the pH of the blood.^[15]

   

  

   
• • Cytoadherence with thrombi formation in glomeruli is a common mechanism of acute kidney injury.^[18]  If anuria or hemoglobinuria (“blackwater fever”) occur, it likely is secondary to an abundance of cell-free hemoglobin that results in reduced renal perfusion. Although contributing to morbidity of the acute illness, most patients do not require long-term dialysis.

   

  

   
• • After infecting a red blood cell, P falciparum can insert adhesive proteins into the erythrocyte membrane, thus creating a cytoadherant phenotype (further described below in ‘species specific nuances’).^[15]  The ability to stick to endothelium, uninfected blood cells, and platelets causes more than 20% of brain capillaries to be filled with P falciparum parasites, resulting in vascular congestion, retinopathy, capillary leakage, thrombi, hemorrhage, axonal injury, coma, and death from cerebral malaria within 48 hours (especially in children). 

   

  

   
• • Occurring with highest incidence in Africa secondary to P falciparum due to its ability to form the cytoadherent phenotype, placental malaria is characterized by the accumulation of infected red blood cells within the intervillous space and ensuing infiltration of maternal macrophages.^[38]  In severe cases, the resulting chronic intravillositis leads to decreased transplacental nutrient transport, fetal growth restriction and low birth weight babies, as well as increased risk for preterm birth and preeclampsia for the mother.^[3]

   

  

   

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Patient Education

Individuals traveling to malarial regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications.^{[1, 3]}

Avoidance

Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and using insect repellants also may prevent infection. Avoid wearing perfumes and colognes.

Mosquito Nets

Bed nets treated with insecticide are more effective in protecting against malaria compared to untreated nets. The insecticides kill and repel mosquitoes, reducing the number of mosquitoes that enter houses and attempt to feed on people. When community coverage is high, the overall mosquito population and their lifespan are reduced, providing protection to all members of the community.

Pregnant patients are at particular risk, as malaria is a frequent cause of miscarriage, preterm delivery, intrauterine growth restriction and low birth weight in endemic countries, and medical preventive measures are not 100% effective.^[39]  Consider using bed nets that are treated with the insecticide permethrin. Although this is an effective method of preventing malaria transmission in endemic areas, an increasing incidence of pyrethroid resistance in Anopheles spp has been reported.^[40]

The WHO has recently published recommendations on two types of insecticide treated nets.

Mosquito Repellant

Although higher concentrations of DEET are heavily marketed, there is no evidence that concentrations of DEET above 50% are more effective^[41]  Lotions containing DEET of 34% (eg Ultrathon - developed for the US military) provides 12 hours of protection and lotion with Picaridin 20% (eg, Sawyer) may provide up to 14 hours of protection. Picaridin has the advantage of being odorless and non-greasy. Both DEET and Picaridin are safe on pregnant women and children >2 months old.

As noted in the section on bed nets, the synthetic pyrethroid, permethrin, also can be sprayed on clothing, tents, and sleeping bags. It remains effective for multiple launderings and has the added advantage of being able to kill mosquitoes and ticks. Permethrin-impregnated clothing also is on the market.

Wearable devices such as wristbands containing various repellants have not been shown to be particularly effective in reducing mosquito attraction (citronella candles combined with human subjects may actually attract mosquitos to a greater degree than human bait alone) - and if staying for a prolonged periods in high-risk malaria-endemic areas (>6 months), topical repellants have only slight efficacy in lowering the overall malaria prevalence.^{[42, 43, 44]}

Illness

Although there is a high risk for febrile traveler's diarrhea whenever traveling a low-resource setting, if the fever does not abate with treatment, seek out medical attention immediately as malaria may present with febrile diarrhea in almost half of cases.^{[45, 46, 47]}

• References

History

In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they traveled to a tropical area at any time in their life may enhance recall. Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.^{[2, 3]}

Also determine the patient's immune status, age, and pregnancy status; allergies or other medical conditions that they may have; and medications that they may be using^[2] .^[3]

Patients with malaria typically become symptomatic a few weeks after infection, although the host's previous exposure or immunity to malaria affects the symptomatology and incubation period. In addition, each Plasmodium species has a typical incubation period. Importantly, virtually all patients with malaria present with headache. Clinical symptoms include the following^{[2, 3]} :

• Cough
• Fatigue
• Malaise
• Shaking chills
• Arthralgia
• Myalgia

Patients experience a paroxysm of fever, shaking chills, and sweats (every 48 or 72 h, depending on species). The classic paroxysm begins with a period of shivering and chills, which lasts for approximately 1-2 hours and is followed by a high fever. Finally, the patient experiences excessive diaphoresis, and the body temperature of the patient drops to normal or below normal.^{[2, 3]}

Many patients, particularly early in infection, do not present the classic paroxysm but may have several small fever spikes a day. Indeed, the periodicity of fever associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale [or tertian fever]; 72 h for P malariae [or quartan fever]) is not apparent during initial infection because of multiple broods emerging in the bloodstream. In addition, the periodicity often is not observed in P falciparum infections. Patients with long-standing, synchronous infections are more likely to present with classic fever patterns. In general, however, the occurrence of periodicity of fever is not a reliable clue to the diagnosis of malaria.^{[2, 3]}

Less common malarial symptoms include the following^{[2, 3]} :

• Anorexia and lethargy
• Nausea and vomiting
• Diarrhea
• Jaundice

Notably, infection with P vivax, particularly in temperate areas of India, may cause symptoms up to 6-12 months after the host leaves the endemic area. Patients infected with P vivax or P ovale may relapse after longer periods, because of the hypnozoite stage in the liver.

P malariae does not have a hypnozoite stage, but patients infected with P malariae may have a prolonged, asymptomatic erythrocytic infection that becomes symptomatic years after leaving the endemic area.

Tertian and quartan fevers are due to the cyclic lysis of red blood cells that occurs as trophozoites complete their cycle in erythrocytes every 2 or 3 days, respectively. P malariae causes quartan fever; P vivax and P ovale cause the benign form of tertian fever; and P falciparum causes the malignant form. The cyclic pattern of fever is very rare.

Travelers to forested areas of Southeast Asia and South America have become infected by Plasmodium knowlesi, a dangerous species normally found only in long-tailed and pigtail macaque monkeys (Macaca fascicularis and M nemestrina, respectively). This species can cause severe illness and death in humans, but, under the microscope, the parasite looks similar to the more benign P malariae and sometimes has been misdiagnosed.

Because P malariae infection typically is relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographic areas who are severely ill and have microscopic evidence of P malariae infection. Diagnosis may be confirmed via polymerase chain reaction (PCR) assay test methods.^{[2, 3]}

• References

Physical Examination

Most patients with malaria have no specific physical findings, but splenomegaly may be present. Symptoms of malarial infection are nonspecific and may manifest as a flulike illness with fever, headache, malaise, fatigue, and muscle aches. Some patients with malaria present with diarrhea and other gastrointestinal (GI) symptoms. Immune individuals may be completely asymptomatic or may present with mild anemia. Nonimmune patients may quickly become very ill.^{[2, 3]}

Severe malaria primarily involves P falciparum infection, although death due to splenic rupture has been reported in patients with non– P falciparum malaria. Severe malaria manifests as cerebral malaria, severe anemia, respiratory symptoms, and renal failure.^[48]  

Patients with severe malaria symptoms such as impaired consciousness, low hemoglobin, organ dysfunction, and high parasite density should receive immediate and aggressive treatment with injectable antimalarial drugs, regardless of the malaria species detected in the blood. In cases where severe malaria is suspected without a confirmed diagnosis, blood should be collected for testing, and treatment should start promptly. Patients under severe malaria treatment should undergo frequent blood smear tests every 12-24 hours until the tests show no presence of Plasmodium parasites.^[48]

In children, malaria has a shorter course, often rapidly progressing to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice.

Please see Pediatric Malaria for more information.

Cerebral malaria

Cerebral malaria (CM), primarily caused by Plasmodium falciparum infection, carries a high mortality rate, and survivors may face long-lasting complications like seizures and neurocognitive deficits. Although the parasite does not directly invade the brain but resides in the bloodstream within brain vessels, the mechanisms underlying neurological issues post-CM remain unclear and require further investigation.

In cases of CM, coma can be a distinguishing feature, and differential diagnosis should consider excluding hypoglycemia and CNS infections. Research by Vera et al showed that children with malaria infection, particularly CM, exhibited higher levels of certain antibodies compared to healthy individuals and those with non-malarial coma. Moreover, elevated antibody levels were associated with lower platelet counts and increased mortality in CM patients. Platelet activation was also higher in CM patients compared to uncomplicated malaria cases, with activation correlating with antibody levels.^[49]

The impact of malaria infections on hemoglobin levels is influenced by various factors, including the presence of unparasitized erythrocytes, bone marrow dyserythropoiesis, and the destruction of infected red blood cells. Children repeatedly infected with malaria may experience progressive anemia due to limited recovery time, whereas some individuals may rapidly decline in hemoglobin levels after a single infection. The recovery of hemoglobin post-infection differs between regions of high and low malaria transmission, reflecting the intricate relationship between malaria and its effects on blood parameters.

Severe anemia

The anemia associated with malaria is multifactorial and usually is associated with P falciparum infection. In nonimmune patients, anemia may be secondary to erythrocyte infection and a loss of infected RBCs. In addition, uninfected RBCs are inappropriately cleared, and bone marrow suppression may be involved.

Renal failure

Renal failure is a rare complication of malarial infection. Infected erythrocytes adhere to the microvasculature in the renal cortex, often resulting in oliguric renal failure. Renal failure typically is reversible, although supportive dialysis often is needed until kidney function recovers. In rare cases, chronic P malariae infection results in nephrotic syndrome.

Respiratory symptoms

Patients with malaria may develop metabolic acidosis and associated respiratory distress, and pulmonary edema can occur. Signs of malarial hyperpneic syndrome include alar flaring, chest retraction (intercostals or subcostal), use of accessory muscles for respiration, or abnormally deep breathing.

• References

Approach Considerations

The presentation of malaria is non-specific (ie, headache, fever, chills, myalgia, nausea, vomiting, diarrhea, fatigue, abdominal pain, altered mentation), and no combination of signs or symptoms can accurately discriminate malaria from other causes of fever in an endemic area. However, malaria should be suspected in any patient presenting with fevers greater than 99.5 degrees Fahrenheit in an endemic area without other obvious cause, as a delay in diagnosis is associated with increased mortality.^{[2, 3]}  

Malaria should be suspected in children if they present with anemia and hemoglobin of less than 8g/dL. The incubation period should be accounted for if the patient of interest is a traveler to an endemic area. The 2 common methods used for parasitological diagnosis include light microscopy and immunochromatographic rapid diagnostic tests that detect parasite-specific proteins, which are discussed in depth below.^[51]

Imaging studies

Chest radiography may be helpful if respiratory symptoms are present. If CNS symptoms are present, a computed tomography (CT) scan of the head may be obtained to evaluate evidence of cerebral edema or hemorrhage.

Microhematocrit centrifugation

Using this method with the CBC tube is a more sensitive method for detection of malaria infection. However, microhematocrit centrifugation does not allow the identification of the species of Plasmodium. To determine species, a peripheral blood smear must be examined.

Fluorescent dyes/ultraviolet indicator tests

Several different dyes allow laboratory results to be obtained more quickly. These methods require the use of a fluorescent microscope. Fluorescent /ultraviolet tests may not yield speciation information.

Polymerase chain reaction assay

PCR assay testing is a very specific and sensitive means of determining if species of Plasmodium are present in the blood of an infected individual. PCR assay tests are not available in most clinical situations. However, they are very effective at detecting the Plasmodium species in patients with parasitemias as low as 10 parasites/mL of blood.

Lumbar puncture

If the patient exhibits mental-status changes, and even if the peripheral smear demonstrates P falciparum, a lumbar puncture should be performed to rule out bacterial meningitis.

• References

Blood Smears

A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear.^[51] The thick smear allows examination of a larger volume of blood and should be used for the detection of malaria parasites (typically able to detect 10-90 parasites/uL of blood depending on expertise - the thin film should be used for species identification and calculation of parasitemia, which influence treatment decisions in the case of P falciparum and P knowlesi infection. 

Film Preparation

See the CDC's Malaria DPDx for blood film preparation and staining guides and videos.

Films should be prepared less than 4 hours after the blood specimen has been drawn, as parasite morphology changes the longer that it is exposed to K₂EDTA (ie, anticoagulated blood).^[52]  

Thick smears​

1. Thick films should be made with 2-3 small drops of blood spread into a circle of 1cm diameter to give 4-6 RBC thickness (ie, it should be possible to read print through the blood film before staining)
2. Allow the slide to dry horizontally at 98.6F for at least 15 minutes or at room temperature for 60 minutes
3. Expose to acetone for 10 minutes in a Coplin staining jar and allow to dry (may help to inactivate enveloped viruses to decrease infection risk to the microscopist) 
4. Place the slide in staining jar with 2.5% working Giemsa for 45-60 minutes (also may use 10% Giemsa for 10 minutes - lesser quality)
5. Place the slide in working Giemsa 7.2 pH buffer for 5 minutes
6. Dry the slide upright in a rack 

Thin smears

1. Thin films should be made with a wide tail by pushing 1 drop of blood across the slide with the end of another clean slide
2. Allow the slide to dry horizontally at 98.6F for at least 15 minutes or at room temperature for 60 minutes
3. Expose the film to acetone for 10 minutes in a Coplin staining jar and allow to dry (may help to inactivate enveloped viruses to decrease infection risk to the microscopist)
4. Fix the thin film in methanol for 30-60 seconds prior to staining with Giemsa
5. Place the slide in staining jar with 2.5% working Giemsa for 45-60 minutes (also may use 10% Giemsa for 10 minutes - lesser quality)
6. Dip the slide 3-4 times in Giemsa 7.2 pH buffer to rinse
7. Dry the slide upright in a rack

Three thick and thin smears 12-24 hours apart should be obtained. When reading a smear, a minimum of 200 high-power fields should be examined by 2 trained observers (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia). One negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period. The highest yield of peripheral parasites occurs during or soon after a fever spike; however, smears should not be delayed while awaiting fever spikes.

Thick smears are more than 10 times more sensitive than thin smears, but species identification is more difficult. Thin smears examined toward the tail end of the blood film where red cells are not overlapping allow for species level identification and quantification of parasitemia. If there is a parasitemia greater than 5%, P falciparum (or infrequently P knowlesi) is the most likely pathogen. 

• References

Alternatives to Blood Smear Testing

Alternative diagnostic methods typically are used if the laboratory does not have sufficient expertise in detecting parasites in blood smears.^[51]

Rapid diagnostic tests (RDT)

Rapid diagnostic tests

Rapid diagnostic tests (RDTs) are portable tests that detect parasite-specific antigens in a blood sample for malaria diagnosis.^[51] They are user-friendly, do not require specialized equipment, and offer quick results. Although they are recommended by the World Health Organization (WHO) for their convenience and benefits, RDTs have limitations such as difficulty in differentiating infections and potential false readings. Despite these challenges, studies have shown the effectiveness of RDTs, especially in detecting P falciparum. Confirming RDT results with a secondary test is advised in cases of low parasite levels or high parasitemias to enhance accuracy in malaria care.^[1]

Various studies have shown that Rapid Diagnostic Tests (RDTs) outperform microscopy in routine conditions, with health facility staff performing RDTs at 91.7% sensitivity and 96.7% specificity, compared to 52.5% sensitivity and 77% specificity for microscopy.While RDTs are effective, they may be less reliable when parasite levels are low or in rare cases where high parasitemias lead to negative RDT results. To enhance accuracy, it is advisable to confirm RDT results with a secondary screening test. Additionally, false-positive RDT outcomes can occur post-treatment due to lingering antigens. RDTs can complement microscopy but a negative result should not conclusively rule out malaria.^[53]   

Continued reliance on HRP2-based RDTs for malaria management could lead to the spread of gene deletions through East Africa by 2050.^[54]  High-risk countries such as Senegal, Zambia, and Kenya have not yet shifted to alternative antigen RDTs and are still vulnerable to pfhrp2/3 gene deletions. While countries like Eritrea, Djibouti, and Ethiopia have initiated the use of pLDH-targeting RDTs, these alternatives have not been widely implemented, lack specificity for distinguishing between P falciparum and P vivax, and do not yet offer the required sensitivity and specificity in the field setting.^[55]

Immunodiagnosis and nucleic acid amplification test methods

Antibody detection for malaria is not precise enough for clinical management, while nucleic acid tests like PCR and loop-mediated isothermal amplification are highly sensitive in detecting low parasite densities and mixed infections.^[51]  These tests are beneficial for research and drug resistance studies but are not widely available or practical for routine diagnosis in malaria-endemic regions due to cost and complexity. Despite their value in population surveys and elimination programs, they are not utilized for clinical management or routine malaria surveillance.^[1]

Immunochromatographic tests utilizing antibodies against histidine-rich protein-2 (PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase demonstrate high sensitivity and specificity.^{[56, 57]} Although only one RDT (BinaxNOW) is approved for malaria diagnosis in the United States,^[58] the WHO advises against exclusive use of HRP2-detecting RDTs in regions with common false-negative rates (>5%) due to HRP2 non-expression.40 The HRP2 knockout phenomenon, initially identified in Peru in 2007 and further in Colombia and Brazil, has been observed in various malaria-endemic areas, raising concerns about its prevalence in countries like Eritrea, Djibouti, and Ethiopia, particularly in the Horn of Africa.^{[1, 4]}

Molecular Diagnostics

In addition to the RDT listed above, molecular techniques such as PCR assay testing and nucleic acid sequence-based amplification are available for diagnosis and species identification.^[51] They are more sensitive than thick smears but are expensive and unavailable in most developing countries.{However, the COVID-19 pandemic has accelerated the expansion of molecular diagnostics to the point that they are now recognized as routine techniques.^[59]  The wider availability of PCR platforms for epidemiologic surveillance, used by military and civilian medical providers across the globe, may bear out to be a providential launchpad for improved malaria detection and eradication.^{[60, 61]}

The US Centers for Disease Control and Prevention (CDC) offers malaria drug-resistance testing for all malaria cases diagnosed in the United States free of charge. Whole blood specimens from all malaria cases diagnosed in the United States should be sent to the CDC Malaria Laboratory for this testing. Please contact malarialab@cdc.gov for information on specimen submission.

The CDC notes that "For some drugs (chloroquine, sulfadoxine-pyrimethamine and similar drugs, atovaquone, artemisinins), molecular markers have been identified that confer resistance. Molecular techniques, such as PCR or gene sequencing can identify these markers in blood taken from malaria-infected patients."^[62]

Malaria is a reportable disease in the USA. Identification of parasites by any of the above techniques should prompt notification to the local or state health department.

• References

Histologic Findings

The table below compares histologic findings for P falciparum, P vivax, P ovale, and P malariae.^[63]

Table 1. Histologic Variations Among Plasmodium Species

View Table

See Table

*Slide images below were retrieved from the CDC DPDx database and are available at no cost - https://www.cdc.gov/dpdx/malaria/index.html 

Plasmodium falciparum

View Image

Thin blood smear showing the ring forms of P falciparum that look like headphones with double chromatin dots. Note how P falciparum is seen infecting ....

View Image

Thick blood smear depicting the banana shaped gametocyte of P falciparum. Multiple ring-form trophozoite precursors are also visible in the background....

Plasmodium vivax

View Image

Thin blood smear of the ring forms of P vivax. Note that P vivax typically has a single chromatin dot vs the two chromatin dots in P falciparum. Court....

View Image

The diagnostic form of P vivax is the amoeboid trophozoite form where the cytoplasm has finger-like projections (pseudopods) without a typical round/o....

Plasmodium ovale

View Image

Thin smear of P ovale in ring stage. Note that typically there is a single chromatin dot, larger cells are infected indicative of reticulocytes, and m....

View Image

Thin smear of P ovale trophozoite. Note that this species is difficult to differentiate from P vivax as it contains CVCs (Schüffner’s dots) and infect....

Plasmodium malariae

View Image

Thin blood smear of “band form” trophozoite of P malariae. Note that the infected erythrocyte is smaller than surrounding cells, indicating that P mal....

Plasmodium knowlesi

View Image

Thin blood smear of P knowlesi trophozoites. An immature ring form is seen on the right next to the mature band form trophozoite on the left. Note the....

• References

Laboratory Studies

Light microscopy

Light microscopy is considered the "field standard" for diagnosing malaria, providing sensitive and specific detection, quantification of parasites, and identification of species. While nucleic acid-based tests are more sensitive, microscopy remains crucial due to its high specificity for diagnosing malaria as the cause of fever. Skilled microscopists can detect low parasite densities, making microscopy effective in diagnosing and monitoring malaria. Despite its advantages, maintaining good microscopy performance requires adequate training, supervision, and resources. Various attempts have been made to enhance malaria microscopy, but traditional Giemsa staining and oil-immersion microscopy remain the preferred method due to their reliable performance in typical healthcare settings.^{[1, 51]}

Microscopy involves examining Giemsa-stained blood smears for identification of Plasmodium species and parasite count. Two slides of each type typically are examined to increase diagnostic accuracy. Results should be available within 2 hours and no later than 24 hours of patient presentation. Microscopy allows for assessing parasite density, which is crucial for determining the severity and prognosis of malaria cases. However, microscopy has limitations, such as difficulty in differentiating between certain Plasmodium species and potential errors in parasite counting, especially in cases of low parasitemia. Although automated systems like the World Health Technology autoanalyzer and Cella Vision DM96 have been developed, manual microscopy by experienced personnel remains the preferred method for precise diagnosis of malaria infections, based on real-time identification of live parasites.^[86]

• References

Approach Considerations

​The treatment of malaria is predicated on the severity of the patient’s illness, the infecting species, geographic knowledge of anti-malarial drug resistance, and knowledge of prior antimalarials given to the patient (it is not recommended to use the same prophylactic medication for treatment).^{[1, 51]}  Prompt malaria treatment is essential, with hospitalization and monitoring for severe cases.^[2]  

Mixed infections involving more than 1 species of Plasmodium may occur in areas of high endemicity and multiple circulating malarial species. In these cases, clinical differentiation and decision making will be important; however, the clinician should have a low threshold for including the possible presence of P falciparum in the treatment considerations.^[2]

Occasionally, morphologic features do not permit distinction between P falciparum and other Plasmodium species. In such cases, patients from a P falciparum –endemic area should be presumed to have P falciparum infection and should be treated accordingly.

In patients from Southeast Asia, consider the possibility of P knowlesi infection. This species frequently causes hyperparasitemia and the infection tends to be more severe than infections with other non– P falciparum plasmodia. It should be treated as P falciparum infection.

P falciparum is resistant to chloroquine treatment except in Haiti, the Dominican Republic, parts of Central America, and parts of the Middle East. Resistance is rare in P vivax infection, and P ovale and P malariae remain sensitive to chloroquine. primaquine or tafenoquine is required in the treatment of P ovale and P vivax infection in order to eliminate the hypnozoites (liver phase).

In the United States, patients with P falciparum infections often are treated on an inpatient basis in order to observe for complications attributable to either the illness or its treatment.

Treatment options for P falciparum infections depend on chloroquine resistance. In chloroquine-resistant areas, options include artemether-lumefantrine, atovaquone-proguanil, quinine plus antibiotics, or mefloquine. Chloroquine remains effective in non-resistant areas. P malariae and P knowlesi infections also may be treated with chloroquine or anti-resistant P falciparum regimens. Additional therapy for hypnozoites is needed for P vivax and P ovale infections, with G6PD testing required before using tafenoquine or primaquine. Artemisinin-based combination therapy, such as artemether-lumefantrine, is recommended for uncomplicated P falciparum malaria. IV artesunate is suitable for pregnant individuals, children, and infants. Close monitoring is necessary for potential complications like delayed hemolytic anemia. Primaquine can prevent relapse in P vivax or P ovale malaria, but caution is needed for G6PD deficient individuals.^{[2, 3]}

Severe malaria

CDC Criteria for Severe Malaria (1 or more of the following) are as follows:

• Impaired consciousness/coma
• Severe anemia (hemoglobin < 7 g/dL)
• Acute kidney injury
• Acute respiratory distress syndrome
• Circulatory collapse/shock
• Disseminated intravascular coagulation
• Acidosis
• Jaundice (along with at least one other sign of severe malaria)
• Percent parasitemia of ≥5%

Severe malaria is characterized by criteria such as impaired consciousness/coma, hemoglobin levels below 7 g/dL, acute kidney injury, acute respiratory distress syndrome, circulatory collapse/shock, acidosis, jaundice (particularly when accompanied by other signs of severe malaria), disseminated intravascular coagulation, and a parasite density of 5% or higher. Patients displaying these symptoms should receive immediate and intensive treatment with injectable antimalarials, even before a laboratory diagnosis confirms the specific malaria species.^[3]

IV artesunate is the recommended treatment for severe malaria, to be given every 12 hours for 24 hours

Pregnancy

Malaria infection during pregnancy poses significant risks for both the pregnant individual and the fetus.^{[2, 3]} Pregnant people, especially first-time mothers, are at a higher risk of contracting malaria. Those infected are more prone to developing severe illness, with P vivax and P falciparum posing significant risks. Complications of malaria during pregnancy include maternal anemia, stillbirths, premature births, fetal growth restriction, low birth weight, developmental issues in the child, and an increased risk for perinatal and infant mortality.^[1]

In 2022, an estimated 12.7 million pregnancies in moderate and high-transmission countries in the WHO African Region were exposed to malaria infection during pregnancy, with the highest prevalence in West and Central Africa, and lower rates in East and Southern Africa. Without pregnancy-specific interventions, over 900,000 neonates were projected to have low birth weight due to malaria infection during pregnancy, stressing the importance of preventive measures such as intermittent preventive treatment during pregnancy (IPTp).

Nonimmune pregnant individuals in endemic areas should utilize appropriate pharmacologic and nonpharmacologic prophylaxis to prevent malaria infections. It is crucial to understand that many antimalarial drugs are safe for use during pregnancy for both the mother and the fetus, making prompt and appropriate treatment essential.

The prevalence of malaria exposure during pregnancy was highest in West Africa (39.3%) and Central Africa (40.1%), with lower rates in East and Southern Africa (27.0%). In the absence of pregnancy-specific interventions, malaria infection during pregnancy in these 33 countries would have resulted in 914,000 neonates with low birth weight. Current coverage levels of IPTp were estimated to lead to around 393,000 neonates with low birth weight in the three subregions.

It is especially important for nonimmune pregnant individuals in endemic areas to use proper pharmacologic and nonpharmacologic prophylaxis to prevent malaria. If a pregnant individual becomes infected, they should be aware that many antimalarial drugs are safe for use during pregnancy for the mother and fetus, highlighting the importance of utilizing these medications as the benefits outweigh the risks of left untreated malaria infection.

Pediatrics

For pediatric patients weighing at least 5 kg, the treatment options for the acute phase of malaria are similar to those for adults, with drug doses adjusted based on the child's weight. The pediatric dose should not exceed the recommended adult dose to ensure safety and efficacy. For children younger than 8 years, doxycycline and tetracycline generally are avoided, necessitating the use of alternative treatment options. In cases involving pediatric patients weighing less than 5 kg, the choices are limited to mefloquine or a combination of quinine and clindamycin. If these options are unavailable or unsuitable, atovaquone-proguanil or artemether-lumefantrine could be considered, provided the benefits outweigh the risks. Additionally, the administration of primaquine to pediatric patients should occur only after screening for G6PD deficiency, and the use of tafenoquine is limited to patients 16 years or older who have received chloroquine treatment.^[64]

In children, malaria has a shorter course, often rapidly progressing to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice.^[64]

Despite modern therapy with artemesinins, ~20% of patients with cerebral malaria die.^[65]

Most antimalarial drugs are very effective and safe in children, provided the proper dosage is administered. Children commonly recover from malaria, even severe malaria, much faster than adults. See the CDC malaria treatment tables for recommended pediatric regimens.

Please see Pediatric Malaria for more information.

Diet and activity

Patients with malaria should continue intake and activity as tolerated.

Monitoring

Even though many patients with non–P falciparum malaria who are well usually tolerate treatment on an outpatient basis - clinicians should consider hospitalizing all patients with malaria for 12-24 hours to verify improvement and medication tolerability. Obtain blood smears every 12-24 hours to demonstrate response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health.

• References

Pharmacologic Therapy

See CDC malaria treatment guideline for dosing specifics and call the malaria hotline for assistance if Infectious Disease consultation is unavailable: A treatment algorithm and treatment tables from the CDC also are available.

CDC Malaria Hotline‎

CDC malaria clinicians are on call 24/7 to provide advice to healthcare providers on the diagnosis and treatment of malaria. Call: (770) 488-7788 or (855) 856-4713 (toll free), M - F, 9 am - 5 pm EST. After hours, weekends, and federal holidays call: (770) 488-7100, ask to speak with the malaria clinician on call. 

​Treatment options for uncomplicated malaria not meeting severe criteria

Updated guidelines for treatment of uncomplicated malaria and treatment of severe malaria were published by the CDC in June 2024. They are summarized below.

P falciparum or unidentified species in areas with chloroquine resistance:

• Artemether-lumefantrine (Coartem®)
• Atovaquone-proguanil (Malarone™)
• Quinine sulfate plus doxycycline, tetracycline, or clindamycin
• Mefloquine

P falciparum in areas without chloroquine resistance:

• Oral chloroquine or hydroxychloroquine
• Any regimen listed for chloroquine-resistant P falciparum malaria

P malariae and P knowlesi:

• Chloroquine or hydroxychloroquine
• Artemether-lumefantrine, atovaquone-proguanil, quinine sulfate plus doxycycline or tetracycline, or mefloquine (if needed)

P vivax and P ovale:

• Chloroquine or hydroxychloroquine (except for chloroquine-resistant areas)
• Artemether-lumefantrine, atovaquone-proguanil, quinine sulfate plus doxycycline or tetracycline, or mefloquine (if needed)
• Primaquine phosphate or tafenoquine (for anti-relapse treatment)

Anti-relapse treatment:

• Primaquine phosphate, tafenoquine (for G6PD-normal patients)
• Adjustments for G6PD-deficient patients

Pediatric dosing:

• Same medications as adults, with doses adjusted by weight
• Dosing considerations for children < 5 kg, mefloquine or quinine plus clindamycin                                

Treatment recommendations for tafenoquine:

Tafenoquine was approved by the FDA in July 2018 for treating P vivax malaria in patients aged 16 years and older with a single oral dose. Testing for G6PD deficiency is necessary before starting tafenoquine due to the risk for hemolytic anemia. Contraindications include G6PD deficiency, breastfeeding an infant with G6PD deficiency, and hypersensitivity.^[66]

In August 2018, tafenoquine received approval for malaria prophylaxis in adults aged 18 years and older traveling to malaria-prone areas with a specific dose regimen.^[67] Combination with chloroquine for the radical cure was recommended in 2020, following successful trials in Indonesian soldiers.

For individuals with G6PD deficiency, moderate cases may require lower-dose primaquine with monitoring, whereas severe deficiency could consider chloroquine prophylaxis for a year post-infection to prevent relapse.^[68] If testing shows G6PD deficiency, a prolonged course of reduced-dosed primaquine may be used for moderate deficiency, whereas chloroquine prophylaxis for a year after acute infection is recommended for severe deficiency.^[17]

Treatment options for severe/ complicated malaria (see CDC severe malaria treatment guideline for dosing specifics)

IV artesunate

Obtain via ivartesunate.com as the CDC no longer provides this medication.

The preferred interim therapy is artemether/lumefantrine (secondary options are atovaquone/proguanil, quinine, and mefloquine).

A dose of of artesunate should be given at 0, 12, and 24 hours.

After the initial course of IV artesunate, the patient can transition to a full course of oral artemether/lumefantrine if parasitemia is reduced to < 1% and the patient tolerates oral therapy.

• If artemether/lumefantrine is unavailable, less preferred options are atovaquone/proguanil, quinine + doxycycline (or clindamycin), or mefloquine (last resort). Doxycycline or clindamycin SHOULD NOT be used as monotherapy as they do not exert anti-parasitic effect for ~24 hours.
• If the patient cannot tolerate oral therapy at the end of the IV artesunate course, the patient can continue receiving artesunate for a duration not to exceed a total of 7 days
• Post-artemesinin hemolytic anemia is a rare adverse effect and is seen to a greater degree in patients with higher initial parasitemia. All patients who receive IV artesunate should be monitored weekly for up to 4 weeks after treatment for evidence of hemolytic anemia^[69] .  Report all post-artesunate hemolysis cases to the US FDA's MEDWATCH.

In a 2010 study conducted in 11 African centers, children with severe P falciparum malaria had lower mortality rates and reduced incidence of coma, seizures, and post-treatment hypoglycemia when treated with IV artesunate compared to IV quinine.^[70] Additionally, a meta-analysis involving 7429 subjects from eight trials showed a decreased risk for death with parenteral artesunate versus quinine for severe malaria in both adults and children.^[71]

P falciparum drug resistance is prevalent in endemic regions, particularly in Africa, rendering standard antimalarials ineffective in many areas. Consequently, the use of combination therapy has become the global norm for treating P falciparum infections. While artemisinins have emerged as a new antimalarial class approved by the US FDA in 2009, monotherapy with these agents is discouraged due to high rates of relapse associated with temporary parasite dormancy after exposure.^[72]

Rectal artesunate is employed as a bridging therapy in resource-limited settings for children awaiting definitive IV or oral treatment.^{[73, 74]} While resistance to artemisinins has been observed in southeast Asia, the FDA officially approved IV artesunate in May 2020 based on studies like SEAQUAMAT and AQUAMAT, which demonstrated reduced mortality rates compared to quinine.^{[70, 75]}

Considering the potential for coinfection with multiple species, including P knowlesi, treatment decisions should account for the likelihood of co-occurring infections. P knowlesi infections have shown a high rate of severe malaria, with IV therapy using quinine or artesunate recommended for severe cases.^{[76, 77]}

Despite their being a fairly new antimalarial class, resistance to artemisinins has been reported in some parts of southeast Asia (Cambodia).^[78]

When making treatment decisions, it is essential to consider the possibility of coinfection with more than 1 species. Reports of P knowlesi infection suggest that coinfection is common.^[76] It also has been demonstrated that up to 39% of patients infected with this species may develop severe malaria. In cases of severe P knowlesi malaria, IV therapy with quinine or artesunate is recommended.^[77]

A note on mefloquine

In July 2013, the FDA updated its warning about mefloquine hydrochloride to include neurologic side effects, along with the already known risk for adverse psychiatric events such as anxiety, confusion, paranoia, and depression. The information, which is included in the patient medication guide and in a new boxed warning on the label, cautions that vestibular symptoms, which include dizziness, loss of balance, vertigo, and tinnitus, can occur.^{[79, 80]}  The FDA also warns that vestibular side effects can persist long after treatment has ended and may become permanent. In addition, clinicians are warned against prophylactic mefloquine use in patients with major psychiatric disorders and are further cautioned that if psychiatric or neurologic symptoms arise while the drug is being used prophylactically, it should be replaced with another medication.

Pharmacologic treatment in pregnancy

In the United States, for uncomplicated chloroquine-resistant P falciparum and P vivax / ovale, artemether-lumefantrine (Coartem) is recommended by the CDC for pregnant patients in all trimesters, as strong evidence demonstrates that it is effective and safe in the treatment of malaria in pregnancy. These data are supported by the World Health Organization.  If artemether-lumefantrine is not available, quinine plus clindamycin can be used, or mefloquine if there are no other options are available. The limited availability of quinine and increasing resistance to mefloquine do limit these options. 

Prophylaxis with weekly chloroquine is recommended after initial treatment if infected during pregancy with P vivax / ovale and antirelapse therapy with primaquine can be considered after delivery. Use of primaquine or tafenoquine to prevent relapse of P vivax malaria during pregnancy is not recommended. Use during pregnancy may cause hemolytic anemia in a G6PD-deficient fetus. In addition, tafenoquine use during lactation should be avoided if the infant is G6PD deficient or of unknown G6PD status.^[66]

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Inpatient Care

Patients meeting criteria for severe malaria or with P falciparum infection initially should be hospitalized until their condition improves and there is a noticeable decline in parasitemia.^{[2, 3]}

Obtain blood smears every 12-24 hours to demonstrate a response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health or cause any symptoms.

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Deterrence and Prevention

Other strategies, including indoor residual spraying and larviciding, are recommended for effective malaria prevention in areas with ongoing transmission and humanitarian emergencies. Recommendations for malaria chemoprevention, mass drug administration, and the RTS,S/AS01 malaria vaccine are provided to reduce malaria burden in different settings. Tailored chemoprophylaxis and treatment based on G6PD status are recommended for pregnant and breastfeeding women.^[3]

Malaria Vaccine

On 6 October 2021, the WHO recommended large-scale use of the RTS,S/AS01 (Mosquirix) malaria vaccine.^{[1, 81]}  It is approved for children in sub-Saharan Africa and other areas with high malaria transmission based on trials involving 830,000 children in Ghana, Kenya, and Malawi. It is a recombinant protein vaccine based on an antigen found on the P falciparum sporozoite. After 30 years of research and development between GlaxoSmithKline and the US Walter Reed Army Institute of Research, its use has resulted in a 9% decrease in all-cause mortality and 30% reduction in hospital admissions of children with severe malaria. If optimal access to the vaccine can be achieved, it is estimated to be able to save the lives of 40,000 to 80,000 African children per year. 

TRAVELERS

Individuals traveling to malaria-endemic regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications.

Avoidance

Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and using insect repellants also may prevent infection. Avoid wearing perfumes and colognes.

Mosquito Nets

Bed nets treated with insecticide, such as permethrin, are more effective in protecting against malaria compared to untreated nets. The insecticides kill and repel mosquitoes, reducing the number of mosquitoes that enter houses and attempt to feed on people. Community-wide coverage of treated bed nets can lower the overall mosquito population and their lifespan, providing protection to all community members.^[40] Pyrethroid-only nets are recommended for malaria prevention in areas with ongoing transmission, while Pyrethroid-PBO nets are advised in regions with malaria vector resistance. Insecticidal nets like Pyrethroid-chlorfenapyr and Pyrethroid-pyriproxyfen are suggested in areas with pyrethroid resistance.^[3]

Pregnant patients are at particular risk, as malaria is a frequent cause of miscarriage, preterm delivery, intrauterine growth restriction and low birth weight in endemic countries, and medical preventive measures are not 100% effective.^[39]  

The WHO has recently published recommendations on two new types of insecticide treated nets.

Mosquito Repellant

Although higher concentrations of DEET are heavily marketed, there is no evidence that concentrations of DEET above 50% are more effective.^[41]  Lotions containing DEET of 34% (eg, Ultrathon - developed for the US military) provides 12 hours of protection and lotion with Picaridin 20% (eg, Sawyer) may provide up to 14 hours of protection. Picaridin has the advantage of being odorless and non-greasy. Both DEET and Picaridin are safe during pregnancy and in children >2 months old.

As noted in the section on bed nets, the synthetic pyrethroid, permethrin, can also be sprayed on clothing, tents, and sleeping bags. It remains effective for multiple launderings and has the added advantage of being able to kill mosquitoes and ticks. Permethrin-impregnated clothing is also on the market.

Wearable devices such as wristbands containing various repellants have not been shown to be particularly effective in reducing mosquito attraction (citronella candles combined with human subjects may actually attract mosquitos to a greater degree than human bait alone) - and if staying for a prolonged periods in high-risk malaria-endemic areas (>6 months), topical repellants have only slight efficacy in lowering the overall malaria prevalence.^{[42, 43, 44]}

Chemoprophylaxis

Consider chemoprophylaxis with antimalarials in patients traveling to endemic areas. Chemoprophylaxis is available in many different forms. The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug.  Adult dosing of primary chemoprophylaxis options are noted below in descending order of preferential use per the author based on geographic coverage, convenience of dosing schedule, and tolerability (cost was not taken into account):

Atovaquone-proguanil (250/100 mg):

• 1 tablet daily with meal, starting 1-2 days prior to entering the malarious area, then daily while in malarious area, then daily for 7 days after leaving the area.

Doxycycline (100 mg) *may concomitantly be effective prophylaxis for respiratory, skin, bacterial STD, leptospira, & rickettsial infection during travel*:

• 1 tablet daily (stay upright for 2 hours after taking to prevent esophagitis), starting 1-2 days prior to entering the malarious area, then daily while in malarious area, then daily for 28 days after leaving the area.
• Monohydrate formulation may be better tolerated than hyclate formulation.

​Tafenoquine (100 mg) *test for G6PD deficiency prior to use*:

• 2 tablets daily for 3 days before entering the malarious area, then wait 7 days to start 2 tablets once weekly while in the malarious area, then (after leaving the malarious area) complete prophylaxis with 2 tablets 1 week after the previous dose.

Mefloquine (250 mg = 228 mg base) *do not use in SE Asia*:

• 1 tablet weekly >2 weeks before entering malarious area (3-4 weeks before if testing for adverse effects), then 1 tablet weekly while in the malarious area, then 1 tablet weekly for 4 weeks after leaving the malarious area. 

​Chloroquine (500mg = 300 mg base) *limited to areas of world without chloroquine resistance*:

• 1 tablet weekly 1-2 weeks prior to entering malarious area, then 1 tablet weekly while in the malarious area, then 1 tablet weekly for 4 weeks after leaving the malarious area.

Primaquine (26.3 mg = 15 mg base) *test for G6PD deficiency & pregnancy prior to use & should use only in areas with predominately P vivax*:

• 2 tablets daily 1-2 days prior to entering the malarious area, then 2 tablets daily while in the malarious area, then 2 tablets daily for 7 days after leaving the malarious area.

Before traveling, people should consult their physician and the Malaria and Traveler's Web site of the CDC to determine the most appropriate chemoprophylaxis.^[83]  Travel Medicine clinics are a useful source of information and advice.

Presumptive Anti-Relapse Therapy

Due to the risk of relapsing malaria from P vivax / ovale hypnozoite formation in the liver, terminal prophylaxis known as presumptive anti-relapse therapy (PART) is recommended when travelers are thought to have had high risk of infection (eg, a traveler with reported high mosquito exposure and incomplete adherence to primary prophylaxis, or a long term traveler to a ​P vivax / ovale endemic area). Although tafenoquine may be used as primary prophylaxis for ​P vivax / ovale infection, the CDC only recommends primaquine for PART (requires G6PD testing and cannot be taken during pregnancy).^{[47, 84]}

In general, when PART is indicated, primaquine should be taken at the end of primary prophylaxis for 14 days, concurrently with the primary prophylaxis regimen. However, adherence is low to non-observed PART with primaquine and either causal prophylaxis with daily primaquine during travel or potentially even "fire-and-forget" causal prophylaxis with tafenoquine - for short term travel - would obviate the need for PART.^{[47, 84]}  

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Consultations

Consider consulting an infectious disease specialist for assistance with malaria diagnosis, treatment, and disease management. The CDC is an excellent resource if no local resources are available. To obtain the latest recommendations for malaria prophylaxis and treatment from the CDC, call the CDC Malaria Hotline at (770) 488-7788 or (855) 856-4713 (M-F, 9 am-5 pm, Eastern time). For emergency consultation after hours, call (770) 488-7100 and ask to talk with a CDC Malaria Branch clinician.^[2]

Pregnant patients with malaria are at increased risk for morbidity and mortality.^{[1, 85]} In addition, nonimmune mothers and immune primigravidas may be at an increased risk for low birth weight, fetal loss, and prematurity. Consult an expert in malaria to determine the safest and most effective prophylaxis or treatment in a pregnant individual.

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Guidelines Summary

Guidelines for the Laboratory Diagnosis of Malaria by the British Society for Haematology were published in March 2022. They are summarized below.^[52]

Films should be prepared less than 4 hours after the blood specimen has been drawn, as parasite morphology changes the longer that it is exposed to K₂EDTA (ie, anticoagulated blood).^[52]  

Thick smears​

• Thick films should be made with 2-3 small drops of blood spread into a circle of 1cm diameter to give 4-6 RBC thickness (ie, it should be possible to read print through the blood film before staining)
• Allow the slide to dry horizontally at 98.6F for at least 15 minutes or at room temperature for 60 minutes
• Expose to acetone for 10 minutes in a Coplin staining jar and allow to dry (may help to inactivate enveloped viruses to decrease infection risk to the microscopist) 
• Place the slide in staining jar with 2.5% working Giemsa for 45-60 minutes (also may use 10% Giemsa for 10 minutes - lesser quality)
• Place the slide in working Giemsa 7.2 pH buffer for 5 minutes
• Dry the slide upright in a rack 

Thin smears

• Thin films should be made with a wide tail by pushing 1 drop of blood across the slide with the end of another clean slide
• Allow the slide to dry horizontally at 98.6F for at least 15 minutes or at room temperature for 60 minutes
• Expose the film to acetone for 10 minutes in a Coplin staining jar and allow to dry (may help to inactivate enveloped viruses to decrease infection risk to the microscopist)
• Fix the thin film in methanol for 30-60 seconds prior to staining with Giemsa
• Place the slide in staining jar with 2.5% working Giemsa for 45-60 minutes (also may use 10% Giemsa for 10 minutes - lesser quality)
• Dip the slide 3-4 times in Giemsa 7.2 pH buffer to rinse
• Dry the slide upright in a rack

Three thick and thin smears 12-24 hours apart should be obtained. When reading a smear, a minimum of 200 high-power fields should be examined by 2 trained observers (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia). One negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period. The highest yield of peripheral parasites occurs during or soon after a fever spike; however, smears should not be delayed while awaiting fever spikes.

Thick smears are more than 10 times more sensitive than thin smears, but species identification is more difficult. Thin smears examined toward the tail end of the blood film where red cells are not overlapping allow for species level identification and quantification of parasitemia. If there is a parasitemia greater than 5%, P falciparum (or infrequently P knowlesi) is the most likely pathogen.^[52]  

Please see the complete guideline for more information.

Guidelines on the Treatment of Uncomplicated Malaria by the CDC were published in June 2024. They are summarized below.

• For P falciparum infections from chloroquine-resistant areas, treatment options include artemether-lumefantrine, atovaquone-proguanil, quinine sulfate plus doxycycline/tetracycline/clindamycin, or mefloquine based on availability and severity.
• Pregnant women and children have specific treatment guidelines.
• Prompt malaria treatment is crucial; in severe cases, hospitalization and frequent monitoring are necessary.
• For infections not identified from chloroquine-resistant regions, chloroquine remains effective; effective regimens must be promptly initiated and adjusted if necessary.
• Malaria infections from P malariae and P knowlesi can be treated with chloroquine or chloroquine-resistant P falciparum regimens.
• P vivax and P ovale infections require additional treatment for hypnozoites, with options including primaquine or tafenoquine.
• Tafenoquine and primaquine use requires G6PD testing due to risk of hemolytic anemia, with alternative approaches for those with intermediate deficiency.
• Tafenoquine and primaquine are contraindicated in pregnancy and specific patient populations.
• Pediatric dosing adjustments and consideration of G6PD status are important in pediatric patients.

See the complete guideline for more information.

Guidelines on the Treatment of Severe Malaria by the CDC were published in March 2024. They are summarized below.

• Criteria for severe malaria include impaired consciousness/coma, hemoglobin < 7 g/dL, acute kidney injury, acute respiratory distress syndrome, circulatory collapse/shock, acidosis, jaundice (with other signs of severe malaria), disseminated intravascular coagulation, and/or parasite density of ≥5%
• Patients with suspected severe malaria should receive prompt and aggressive treatment with parenteral antimalarials, even before the laboratory diagnosis confirms the malaria species
• IV artesunate is the recommended treatment for severe malaria, to be given every 12 hours for 24 hours
• Interim oral treatment with artemether-lumefantrine may be used while waiting for IV artesunate
• Following IV artesunate treatment, patients can transition to oral treatment if parasite density is ≤1%, using medications like artemether-lumefantrine, atovaquone-proguanil, quinine plus doxycycline or clindamycin, or mefloquine
• Pregnant women, children, and infants can also be treated with IV artesunate
• Complications such as delayed post-artemisinin hemolytic anemia may occur after IV artesunate treatment, requiring close monitoring and potential blood transfusion
• Exchange transfusion is no longer recommended as an adjunct treatment for severe malaria by the CDC

See the complete guideline for more information.

Malaria Treatment Guidelines by the World Health Organization were published October 16, 2023. They are summarized below. https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria 

• Pyrethroid-only nets are recommended for malaria prevention and control in areas with ongoing transmission, while Pyrethroid-PBO nets are advised for regions where malaria vectors exhibit resistance.
• Different types of insecticidal nets, such as Pyrethroid-chlorfenapyr and Pyrethroid-pyriproxyfen, are suggested for areas with pyrethroid resistance, with specific recommendations based on the situation.
• Various strategies, including indoor residual spraying and larviciding, are recommended for effective malaria prevention, especially in areas with ongoing transmission and humanitarian emergencies.
• Recommendations regarding malaria chemoprevention, mass drug administration, and the use of the RTS,S/AS01 malaria vaccine are provided to reduce malaria burden and transmission in different epidemiological settings.
• Proper diagnosis and management of malaria cases, including the use of parasitological tests and quality assurance programs, are emphasized for accurate treatment and control of the disease.
• Artemisinin-based combination therapy should be used to treat uncomplicated P falciparum malaria in children and adults. The recommended combinations include artemether-lumefantrine (AL), artesunate-amodiaquine (AS+AQ), artesunate-mefloquine (ASMQ), dihydroartemisinin-piperaquine (DHAP), artesunate + sulfadoxine-pyrimethamine (AS+SP), and the more recent addition of artesunate-pyronaridine (ASPY) in 2022. These drug combinations are effective and recommended for managing cases of uncomplicated malaria caused by P falciparum.
• Artesunate-pyronaridine (ASPY) is recommended for uncomplicated P falciparum malaria in 2022.
• Revised dosing for dihydroartemisinin + piperaquine in young children.
• Single-dose primaquine with an ACT in low-transmission areas for P falciparum malaria.
• Artemether-lumefantrine for pregnant women with P falciparum malaria in the first trimester.
• ACT for infants under 5 kg with uncomplicated P falciparum malaria.
• ACT for non-immune travelers with uncomplicated P falciparum malaria.
• Close monitoring and ACT treatment for individuals with P falciparum hyperparasitaemia.
• Species-specific treatment considering chloroquine susceptibility, with ACT in areas with resistance.
• Primaquine for P vivax or P ovale malaria prevention with duration considerations.
• Varied primaquine regimens to prevent P vivax or P ovale malaria relapse.
• Primaquine use in G6PD deficient individuals with medical oversight.
• Tailored chemoprophylaxis and treatment based on G6PD status for pregnant and breastfeeding women.

Please see the complete guideline for more information.

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Medication Summary

The 4 major drug classes used to treat malaria include quinoline-related compounds, antifolates, artemisinin derivatives, and antimicrobials. No single drug that can eradicate all forms of the parasite's life cycle has been discovered or manufactured yet; therefore, 1 or more classes of drugs often are given at the same time to combat malarial infection synergistically. Treatment regimens are dependent on the geographic location of infection, the likely Plasmodium species, and the severity of disease presentation.^{[2, 3]}

Beware of counterfeit antimalarial drugs being taken by patients that may have been purchased overseas or via the internet. They may not contain any active ingredients at all and may contain dangerous materials.

Antipyretics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), are indicated to reduce the level of discomfort caused by the infection and to reduce fever. NSAIDs should be used with caution if bleeding disorder or hemolysis is suspected.

Antimalarials can cause significant prolongation of the QT interval, which can be associated with an increased risk for potentially lethal ventricular dysrhythmias. Patients receiving these drugs should be assessed for QT prolongation at baseline and carefully monitored if this is present. Patients with normal QT intervals on electrocardiogram (ECG) may not be at a significantly increased risk for drug-induced dysrhythmia, but caution is advised, particularly if the patient is taking multiple drug regimens or if they are on other drugs affecting the QT interval.

Methemoglobinemia is a complication that may be associated with high-dose regimens of quinine or the derivatives chloroquine and primaquine.^[78] A patient presenting with cyanosis and a normal PaO2 on room air should be suspected of having methemoglobinemia.

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Chloroquine phosphate (Aralen)

• Dosing, Interactions, etc.

Clinical Context:  Chloroquine phosphate is effective against P vivax, P ovale, P malariae, and drug-sensitive P falciparum. It can be used for prophylaxis or treatment. This is the prophylactic drug of choice for sensitive malaria.

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Quinine (Qualaquin)

• Dosing, Interactions, etc.

Clinical Context:  Quinine is used for malaria treatment only; it has no role in prophylaxis. It is used with a second agent in drug-resistant P falciparum. For drug-resistant parasites, the second agent is doxycycline, tetracycline, pyrimethamine sulfadoxine, or clindamycin.

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Quinidine gluconate

• Dosing, Interactions, etc.

Clinical Context:  Quinidine gluconate is indicated for severe or complicated malaria and is used in conjunction with doxycycline, tetracycline, or clindamycin. Quinidine gluconate can be administered IV and is the only parenterally available quinine derivative in the United States.

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Doxycycline (Vibramycin, Adoxa, Doryx)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is used for malaria prophylaxis or treatment. When it is administered for treatment of P falciparum malaria, this drug must be used as part of combination therapy (eg, typically with quinine or quinidine).

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Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Tetracycline may specifically impair the progeny of apicoplast genes, resulting in their abnormal cell division. Loss of apicoplast function in progeny of treated parasites leads to slow, but potent, antimalarial effect.

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Clindamycin (Cleocin HCl, Cleocin Phosphate)

• Dosing, Interactions, etc.

Clinical Context:  Clindamycin is part of combination therapy for drug-resistant malaria (eg, typically with quinine or quinidine). It is a good second agent in pregnant patients.

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Mefloquine

• Dosing, Interactions, etc.

Clinical Context:  Mefloquine acts as a blood schizonticide. It may act by raising intravesicular pH within the parasite's acid vesicles. Mefloquine is structurally similar to quinine. It is used for the prophylaxis or treatment of drug-resistant malaria. It may cause adverse neuropsychiatric reactions and should not be prescribed for prophylaxis in patients with active or recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.

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Atovaquone and proguanil (Malarone)

• Dosing, Interactions, etc.

Clinical Context:  Atovaquone may inhibit metabolic enzymes, which in turn inhibits the growth of microorganisms.

Used for pediatric patients, this combination should be administered for uncomplicated P falciparum; can also be used in combination with chloroquine.

This agent is approved in the United States for the prophylaxis and treatment of mild chloroquine-resistant malaria. It may be a good prophylactic option for patients who are visiting areas with chloroquine-resistant malaria and who cannot tolerate mefloquine. Each tab combines 250 mg of atovaquone and 100 mg of proguanil hydrochloride. The dosage for children is based on body weight; in children 40 kg (88 lb) or less, a lower-dose pediatric tablet (62.5 mg of atovaquone and 25 mg of proguanil hydrochloride) is available.

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Primaquine

• Dosing, Interactions, etc.

Clinical Context:  Primaquine is not used to treat the erythrocytic stage of malaria. Administer the drug for the hypnozoite stage of P vivax and P ovale to prevent relapse.

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Artemether and lumefantrine (Coartem)

• Dosing, Interactions, etc.

Clinical Context:  This drug combination is indicated for the treatment of acute, uncomplicated P falciparum malaria. It contains a fixed ratio of 20 mg artemether and 120 mg lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartemisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta hematin.

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Artesunate

• Dosing, Interactions, etc.

Clinical Context:  Artesunate, a form of artemisinin, is rapidly metabolized to active metabolite, dihydroartemisinin (DHA). Artesunate and DHA, like other artemisinins, contain an endoperoxide bridge that is activated by heme iron, leading to oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and decreased parasite growth and survival. It is indicated for initial treatment of severe malaria in adults and children. Once the patient can tolerate oral therapy, a complete treatment course of an appropriate oral antimalarial regimen should always follow artesunate.

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Tafenoquine (Arakoda, Krintafel)

• Dosing, Interactions, etc.

Clinical Context:  Tafenoquine is an 8-aminoquinoline derivative. The 150-mg tablet (Krintafel) is indicated for the radical cure (prevention of relapse) of P vivax malaria in patients aged 16 years or older who are receiving appropriate antimalarial therapy for acute P vivax infection. Krintafel is administered as a single 300-mg dose coadministered on the first or second day of appropriate antimalarial therapy. The drug is active against all stages of the P vivax life cycle, including hypnozoites.

Tafenoquine is also indicated for adults aged 18 years or older as prophylaxis when traveling to malarious areas. For this indication, the 100-mg tablet (Arakoda) is administered as a loading dose (before traveling to endemic area), a maintenance dose while in malarious area, and then a terminal prophylaxis dose in the week exiting the area.

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Class Summary

These agents inhibit growth by concentrating within acid vesicles of the parasite, increasing the internal pH of the organism. They also inhibit hemoglobin utilization and parasite metabolism.

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