Malaria

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. ^[2]  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. ^[3]  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. ^[4]
• 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. ^[2]
• 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. ^[5]  Malaria eventually was eradicated from the United States in 1951, yet the Anopheles vector persists. ^[6]  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. ^[7]  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. ^[8]

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. ^[9]  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.

There are 4 common Plasmodium species of concern to humans. There is a fifth in Southeast Asia that rarely can infect humans and cause severe disease, Plasmodium knowlesi; however, this species typically causes simian malaria. The overwhelming majority of worldwide morbidity from malaria is caused by P falciparum and to a lesser degree, P vivax.[1, 10]    

Biology

Figure 1. Malaria life cycle

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

Stages of Infection

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.

Species Specific Nuances

P falciparum

• ​Typical incubation period: 8-11 days ^[11]
• Classic fever periodicity: 36-48 hours
• Unique syndromes and mechanisms

  • 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. ^[12]  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) ^[11]
• Classic fever periodicity: 48 hours
• Unique syndromes and mechanisms

  • 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. ^[13]  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. ^[14]
  • P vivax infects reticulocytes preferentially via the Duffy antigen present on red blood cells. ^{[15, 16]}  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) ^[11]
• Classic fever periodicity: 48 hours
• Unique syndromes and mechanisms

  • 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). ^{[10, 11]}

P malariae

• Typical incubation period: 18-40 days
• Classic fever periodicity: 72 hours
• Unique syndromes and mechanisms

  • P malariae infections typically cause lower parasitemia and account for a minority of the malaria burden in the world. ^[10]  P malariae infection also is associated with proteinuria and membranoproliferative glomerulonephritis secondary to immune complex deposition. ^[11]  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  ^[11]
• Classic fever periodicity: 24-27 hours
• Unique syndromes and mechanisms

  • 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.

Per the WHO, as of 2021 malaria was endemic in 84 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.[17]  In these patients, there is a 14% risk for severe disease, and 13% of the cases initially are misdiagnosed.

Epidemiologic measures[15]

• 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

• 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. ^[18]  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: CO ₂, 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.
• Transmission intensity typically is measured by parasite incidence. The varying degrees are characterized as follows:

  • 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

• 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.

Proportion of 2021 Global Malaria Burden. Gray area accounts for the remaining estimated 4.4% of worldwide malaria burden. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

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 as the primary infection. The map does not include confirmed “mixed infections.” Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

North America

North American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

South America

South American Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

Europe

Per the WHO 2022 World Malaria Report, no 2021 case data exists for the European region.[1]  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.[19]

Africa

African Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

Asia & South Pacific

Asian and Oceanic Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

South Pacific Presumed and Confirmed Malaria Cases 2021. Gray indicates that there were either no data available or there were zero endemic cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

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]

• 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. ^{[15, 16]}  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.   ^[10]

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 indicates higher proportion of P vivax cases, whereas blue indicates higher proportion of P falciparum cases. Map created using data adapted from WHO 2022 World Malaria Report [https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022].

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.

Mortality

In 2021, 247 million malaria cases occurred globally with 619,000 deaths, 96% of which occurred in the African region.[1]  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. ^[20]  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.
• 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.

Sex-Related

• Recent public health data from a malaria endemic region of Africa (Uganda) suggest that females of child-bearing age (15-39 years) are at increased risk for suspected malaria compared with other sex/age demographics, although males in that same age group and older have significantly higher test positivity. ^[21]  Females in the study had almost twice the incidence of malaria compared with males. However, the authors noted that females in the study were also more than twice as likely to visit their local health facility for a recent fever as compared with males. Finally, there was also a higher incidence of non-malaria-related healthcare visits among females in general.
• 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. ^[22]  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. ^[21]  This evidence suggests the presence of sex differences regarding acquisition of immunity to malaria. 

Genetics-Related

• Hemoglobinopathies

  • 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. ^[23]  This is especially true in geographic regions of Africa where malaria transmission is higher. ^[24]  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. ^[25]  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

  • 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. ^[24]  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. ^[26]  The prevalence of the protective polymorphisms of G6PD deficiency also are associated with malaria transmission intensity in endemic countries.
• Blood Group Antigens

  • Apart from P vivax requiring the Duffy antigen for erythrocyte entry, the risk conferred by other blood groups has been elucidated. ^[16]  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%. ^[27]

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.[12]  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.

• Fever

  • 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. ^{[11, 28]}  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. ^[29]  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.
• Anemia

  • 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. ^[30]  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.
• Splenomegaly

  • During acute malaria infection, the spleen serves as the main driver of infected erythrocyte clearance, immune cell activation, and extramedullary hematopoiesis. ^[31]  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. ^[32]
• Acidosis

  • 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. ^[12]
• Renal Injury

  • Cytoadherence with thrombi formation in glomeruli is a common mechanism of acute kidney injury. ^[15]  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.
• Cerebral malaria

  • 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’). ^[12]  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). 
• Placental malaria

  • 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. ^[33]  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.

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

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.

Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when the skin no longer is exposed to potential mosquito bites. 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.[34] Seek out medical attention immediately upon contracting any tropical fever or flulike illness.

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.

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.

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:

• 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.

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.

Less common malarial symptoms include the following:

• 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.

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.

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.

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.

Cerebral malaria

This feature almost always is caused by P falciparum infection. Coma may occur; coma usually can be distinguished from a postictal state secondary to generalized seizure if the patient does not regain consciousness after 30 minutes. When evaluating comatose patients with malaria, hypoglycemia and CNS infections should be excluded.

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.

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.[18]  Malaria should be suspected in children if they present with anemia and hemoglobin of less than 8g/dL. As described in the differential diagnosis section, 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.

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.

A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear. 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).[36]  

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. 

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

Rapid diagnostic tests (RDT)

Immunochromatographic tests based on antibody to histidine-rich protein-2 (PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase appear to be very sensitive and specific.[37, 38]  Only 1 RDT (BinaxNOW) has been approved for the diagnosis of malaria in the United States.[39] However, per WHO guidance, HRP2-detecting RDTs should not be used exclusively in areas where false-negative RDT rates due to non-expression of HRP2 are common (>5%).[40]  The HRP2 knockout phenomenon originally was identified in Peru in 2007, then subsequently in Columbia and Brazil, but it has been found in many other malaria-endemic areas, with a major concern for high prevalence (>80% in P falciparum) in countries in the Horn of Africa (Eritrea, Djibouti, Ethiopia).[1, 2]

In other studies, RDTs have performed better than microscopy under routine conditions. RDTs performed by the health facility staff were 91.7% sensitive and 96.7% specific; microscopy was 52.5% sensitive and 77% specific.[41] A study using loop-mediated amplification technique (LAMP) also suggests that RDTs have accuracy similar to that of nested PCR, with a greatly reduced time to result, and was superior to expert microscopy.[42]

In a study from Tanzania, d'Acremont et al reported that antimalarials could be safely withheld from febrile children (< 5 y) who had negative results from an RDT based on PfHRP2.[43]

RDTs are less effective when parasite levels are below 100 parasites/mL of blood, and, in rare instances, an RDT test is negative in patients with high parasitemias. For these reasons, confirm RDT test results with a second type of screening test when possible. A false-positive result from an RDT may occur up to 2 weeks or more after treatment due to persistence of circulating antigens.

In summary, RDTs should supplement microscopy and can be helpful; however, a negative result does not rule out malaria.

Other tests

In addition to the RDT listed above, new molecular techniques, such as PCR assay testing and nucleic acid sequence-based amplification (NASBA), are available for diagnosis and species identification. They are more sensitive than thick smears but are expensive and unavailable in most developing countries.[44]

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

The table below compares histologic findings for P falciparum, P vivax, P ovale, and P malariae.

Table 1. Histologic Variations Among Plasmodium Species (Open Table in a new window)

*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

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 erythrocytes of all ages – a trait that can be utilized by the microscopist by noting the similar size of infected erythrocytes to other surrounding uninfected erythrocytes. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

Thick blood smear depicting the banana shaped gametocyte of P falciparum. Multiple ring-form trophozoite precursors are also visible in the background. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

Plasmodium vivax

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

The diagnostic form of P vivax is the amoeboid trophozoite form where the cytoplasm has finger-like projections (pseudopods) without a typical round/oval structure. These pseudopods are unique to P vivax. Numerous small pink-red dots are also seen in both P vivax and P ovale; these are known as caveola-vesicle complexes (CVCs or Schüffner’s dots) and are composed of numerous flask-like indentations on infected reticulocytes membrane skeleton associated with tube-like vesicles. CVCs are thought to play a role in nutrient uptake or release of metabolites from parasite-infected erythrocytes. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

Plasmodium ovale

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 multiple ring forms may be present intracellularly. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

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 infects reticulocytes; a notable unique characteristic of P ovale is the presence of fimbriae on the reticulocyte membrane, which are even more likely to be seen in gametocyte infected red blood cells. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

Plasmodium malariae

Thin blood smear of “band form” trophozoite of P malariae. Note that the infected erythrocyte is smaller than surrounding cells, indicating that P malariae infects older erythrocytes. As the trophozoite matures, the cytoplasm elongates and dark pigment granules of hemozoin are visualized toward the periphery. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

Plasmodium knowlesi

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 small size of the infected red blood cells and how the band form is similar in appearance to P malariae. Courtesy of the Centers for Disease Control and Prevention (CDC) [https://www.cdc.gov/dpdx/malaria/index.html].

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).

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

• 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%

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.

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.

Pregnancy

Pregnant women, especially primigravid women, are up to 10 times more likely to contract malaria than nongravid women. Gravid women who contract malaria have a greater tendency to develop severe malaria. Unlike malarial infection in nongravid individuals, pregnant individuals with P vivax are at high risk for severe malaria, and those with P falciparum have a greatly increased predisposition for severe malaria as well.

For these reasons, it is especially important that nonimmune pregnant persons in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis.

If a pregnant individual becomes infected, they should know that many of the antimalarial and antiprotozoal drugs used to treat malaria are safe for use during pregnancy for the mother and the fetus. Therefore, the medications should be used, since the benefits of these drugs greatly outweigh the risks associated with leaving the infection untreated.

In the United States, treatment options for uncomplicated chloroquine-resistant P falciparum and P vivax malaria in pregnant individuals are limited to mefloquine or quinine plus clindamycin. Although the limited availability of quinine and increasing resistance to mefloquine limit these options, strong evidence demonstrates that artemether-lumefantrine (Coartem) is effective and safe in the treatment of malaria in pregnancy. These data are supported by the World Health Organization.

The CDC recommends the use of artemether/lumefantrine as an additional treatment option for uncomplicated malaria in pregnant patients in the United States during the second and third trimester of pregnancy at the same doses recommended for nonpregnant patients. During the first trimester of pregnancy, mefloquine or quinine plus clindamycin should be used as treatment; however, when neither of these options is available, artemether-lumefantrine should be considered.[45]

Pediatrics

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.

Cerebral malaria results in neurologic sequelae in 9-26% of children, but of these sequelae, approximately one half completely resolve with time.

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.

Diet and activity

Patients with malaria should continue intake and activity as tolerated.

Monitoring

Patients with non– P falciparum malaria who are well usually can be treated on an outpatient basis. Obtain blood smears every day 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.

​Treatment options for uncomplicated malaria not meeting severe criteria (see CDC malaria treatment guideline for dosing specifics)[14]  

P falciparum or Species Not Identified from area with chloroquine resistance

• Artemether/lumefantrine
• Atovaquone/proguanil
• Quinine (extended duration if infection acquired in SE Asia) + doxycycline (doxycycline is preferred, but tetracycline or clindamycin also are options)
• Mefloquine (not recommended in certain regions of SE Asia due to resistance)

P falciparum from area without chloroquine resistance or other Species Not Identified (P vivax, ovale, malariae, knowlesi)

• Chloroquine
• Hydroxychloroquine
• Any regimen listed for chloroquine-resistant P falciparum malaria

*P vivax chloroquine resistance has been noted with high prevalence in Papua New Guinea and Indonesia, and cases arising from these areas should not be treated with chloroquine.

• Otherwise, P vivax initially may be treated with chloroquine with potential transition to a regimen reserved for chloroquine resistance, as rare cases of chloroquine resistance also have been found in Burma, India, and South America.

P vivax & P ovale hypnozoite eradication (must test for G6PD Deficiency)

• Primaquine daily for 14 days (can start with treatment of acute infection)
• Tafenoquine single dose only in patients >16 years who received chloroquine for treatment of acute infection                                                 

Treatment recommendations for tafenoquine:

In July 2018, the FDA approved tafenoquine, an antiplasmodial 8-aminoquinoline derivative 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. The drug is active against all stages of the P vivax life cycle. Tafenoquine is administered as a single oral dose on the first or second day of appropriate antimalarial therapy (chloroquine) for acute P vivax malaria. Because tafenoquine increases the risk for hemolytic anemia in patients with G6PD deficiency, patients must be tested before initiating the drug. Tafenoquine is contraindicated in patients with G6PD deficiency (or unknown status), in patients who are breastfeeding an infant with G6PD deficiency (or unknown status), and in those with known hypersensitivity.[46]  In August 2018, tafenoquine gained a second indication 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.[47]

The recommendation to use tafenoquine for radical cure only in combination with chloroquine was made in 2020 following the unpublished results of a randomised trial of tafenoquine versus low-dose primaquine versus placebo in Indonesian soldiers returning from Papua (artemesinin combination therapy is the recommended blood stage therapy in Indonesia). The rationale for only using tafenoquine with chloroquine may be explained by either suboptimal dosing in the randomized trials or synergy of the 8-aminoquinolones with chloroquine.[48]

If G6PD testing indicates deficiency, moderate deficiency can be treated with a prolonged course of reduce-dosed primaquine with close monitoring for hemolysis. If G6PD deficiency is severe, chloroquine prophylaxis may be used for a 1 year duration after acute infection given that most reactivations occur in this period.[13]

Treatment options for severe/ complicated malaria (see CDC 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)
• 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. 

In a 2010 randomized study done in 11 African centers, children (age < 15 years) with severe P falciparum malaria had reduced mortality after treatment with IV artesunate, as compared with IV quinine. Development of coma, seizures, and posttreatment hypoglycemia were each less common in patients treated with artesunate.[49]

Evidence from a meta-analysis including 7429 subjects from 8 trials shows a decreased risk for death using parenteral artesunate compared with quinine for the treatment of severe malaria in adults and children.[50]

P falciparum drug resistance is common in endemic areas, such as Africa. Standard antimalarials, such as chloroquine and antifolates (pyrimethamine/sulfadoxine), are ineffective in many areas. Because of this increasing prevalence of drug resistance and a high likelihood of resistance development to new agents, combination therapy is becoming the standard of care for treatment of P falciparum infection worldwide. In April 2009, the US Food and Drug Administration (FDA) approved the use of artemisinins, a new class of antimalarial agent.[51]

Despite the activity of artemisinin and its derivatives, monotherapy with these agents has been associated with high rates of relapse. This may be due to the temporary arrest of the growth of ring-stage parasites (dormancy) after exposure to artemisinin drugs. For this reason, monotherapy with artemisinin drugs is not recommended.[52] Rectal artesunate has been used for pretreatment of children in resource-limited settings as a bridge therapy until the patient can access health care facilities for definitive IV or oral therapy.[53]

Despite their being a fairly new antimalarial class, resistance to artemisinins has been reported in some parts of southeast Asia (Cambodia).[54]

Artesunate IV was officially approved by the FDA in May 2020 (it was previously available from the CDC through an IND protocol). Approval was based the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine Artesunate Malaria Trial (AQUAMAT). These 2 studies examined a total of 6,886 patients, including adults, children, and pregnant women. Artesunate IV reduced mortality by 34.7% (P = 0.0002) and 22.5% (P = 0.002) compared with quinine in the SEAQUMAT and AQUAMAT studies, respectively.[49, 55]

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.[56] 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.[57]

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.[58, 59]  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

Medications that can be used for the treatment of malaria in pregnancy include chloroquine, quinine, atovaquone-proguanil, clindamycin, mefloquine, sulfadoxine-pyrimethamine (avoid in first trimester) and the artemisinins (see below). Briand et al compared the efficacy and safety of sulfadoxine-pyrimethamine to mefloquine for intermittent preventive treatment during pregnancy. In their study, 1601 women of all gravidities received either sulfadoxine-pyrimethamine (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or mefloquine (15 mg/kg) in a single dose twice during pregnancy. There was a small advantage for mefloquine in terms of efficacy, although the incidence of side effects was higher with mefloquine than with sulfadoxine-pyrimethamine.[60, 61]  

In addition to mefloquine and sulfadoxine/pyrimethamine, other medications have been used in the treatment of the pregnant patient with malaria. In a recent study in African patients, artemether/lumefantrine was as efficacious and as well tolerated as oral quinine in treating uncomplicated falciparum malaria during the second and third trimesters of pregnancy.[62]  Artesunate and other antimalarials also appear to be effective and safe in the first trimester of pregnancy, when development of malaria carries a high risk for miscarriage.[63]  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.[46]

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.

Obtain blood smears every day 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.

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.

Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when the skin no longer is exposed to potential mosquito bites. Consider using bed nets that are treated with the insecticide permethrin. Although this is an effective method for prevention of malaria transmission in endemic areas, an increasing incidence of pyrethroid resistance in Anopheles spp has been reported.[34] Seek out medical attention immediately upon contracting any tropical fever or flulike illness.

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.

Before traveling, people should consult their physician and the Malaria and Traveler's Web site of the CDC to determine the most appropriate chemoprophylaxis.[64] Travel Medicine clinics are a useful source of information and advice.

Malaria Vaccine

On 6 October 2021, the WHO recommended large-scale use of the RTS,S/AS01 (Mosquirix) malaria vaccine.[1, 65]  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. 

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.[66]

Pregnant patients with malaria are at increased risk for morbidity and mortality.[40] 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.

British Society for Haematology Guidelines for the Laboratory Diagnosis of Malaria

CDC Malaria Treatment Guidelines

WHO Malaria Treatment Guidelines

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.

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.[54] A patient presenting with cyanosis and a normal PaO2 on room air should be suspected of having methemoglobinemia.

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.

Chloroquine phosphate (Aralen)

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.

Quinine (Qualaquin)

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.

Quinidine gluconate

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.

Doxycycline (Vibramycin, Adoxa, Doryx)

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).

Tetracycline

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.

Clindamycin (Cleocin HCl, Cleocin Phosphate)

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.

Mefloquine

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.

Atovaquone and proguanil (Malarone)

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.

Primaquine

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.

Artemether and lumefantrine (Coartem)

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.

Artesunate

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.

Tafenoquine (Arakoda, Krintafel)

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.