Malaria is an ancient and continuously unmatched parasitic cause of human suffering throughout the world. Plasmodiumspp, 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. It continues to wreak havoc, targeting and killing the most vulnerable in our global society.
Signs and Symptoms
Diagnosis
Management
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.
Implications on civilization include the following:
The following were significant in the discovery of malaria:
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]
Figure 1. Malaria life cycle
Stages of Infection
Infection
Exoerythrocytic Schizogeny – “Liver Stage”
Erythrocytic Schizogeny - “Blood Stage”
Sporogony - “Mosquito Stage”
P falciparum
P vivax
P ovale
P malariae
P knowlesi
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]
Transmission
Geography of modern disease burden
The maps below were generated using data obtained from the WHO 2022 World Malaria Report.
North America
South America
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
Asia & South Pacific
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]
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.
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.
Genetic variation and population dynamics play a prominent role in the global patterns of malaria prognosis and epidemiology.
Age-Related
Sex-Related
Genetics-Related
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.
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.
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.
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 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.
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.
Malaria is the most common life-threatening cause of fever in a returning traveler from malaria-endemic countries.[35] Given the potential for relapse or delayed primary infection from P vivax or ovale, malaria always should be ruled out if the patient has an epidemiologic travel link over the prior several months. Remeber that a consideration for malaria should occur for any fever in a traveler from an endemic area, as the disease may present with other ailments concomitantly, or the patient may experience unique malaria-related protean manifestations of their own.
Etiologies of travel-related fever may be classified in a clinically useful fashion through the understanding of specific infectious diseases’ incubation periods. Once a proper timeframe of expected disease presentation is established, the list of differential diagnoses may be narrowed further by the geography of the patient’s itinerary and likely transmission risks. Below are lists of diseases associated with their usual incubation periods:
Incubation period < 14 days
Incubation period 14-42 days
Incubation period >42 days
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.
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.
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.
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.
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.
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
Thin smears
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.
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.
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)
Findings |
P falciparum |
P vivax |
P ovale |
P malariae |
Only early forms present in peripheral blood |
Yes |
No |
No |
No |
Poly-infected RBCs |
Often |
Occasionally |
Rare |
Rare |
Age of infected RBCs |
RBCs of all ages |
Young RBCs |
Young RBCs |
Old RBCs |
Schüffner dots |
No |
Yes |
Yes |
No |
Other features |
Cells have thin cytoplasm, 1 or 2 chromatin dots, and applique forms. |
Late trophozoites develop pleomorphic cytoplasm. |
Infected RBCs become oval, with tufted edges. |
Bandlike trophozoites are distinctive. |
*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
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Plasmodium knowlesi
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):
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.
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]
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.
Patients with malaria should continue intake and activity as tolerated.
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
P falciparum from area without chloroquine resistance or other Species Not Identified (P vivax, ovale, malariae, knowlesi)
*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.
P vivax & P ovale hypnozoite eradication (must test for G6PD Deficiency)
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.
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.
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.
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 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 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 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 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 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 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 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 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 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.
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, 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 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.
Overview
What are the signs and symptoms of malaria?
Which physical findings suggest malaria?
What should be the focus of patient history in suspected malaria?
Which blood studies should be performed in the workup of malaria?
What is the role of imaging studies in the workup of malaria?
What is the role of lab testing in the workup of malaria?
How are Plasmodium species histologically distinguished?
What is the basis for treatment selection in patients with malaria?
What are the general recommendations for pharmacologic treatment of malaria?
Which medications are used for the treatment of malaria in pregnancy?
Where is malaria most prevalent and how is malaria infection transmitted?
Which Plasmodium species cause malaria?
How are Plasmodium species that cause malaria differentiated?
How common is malaria infection caused by multiple Plasmodium species?
Who is at increased risk for malaria infection?
What is the pathogenesis of malaria?
What complications are associated with Plasmodium falciparum (P falciparum) malarial infection?
How is malaria infection transmitted?
What are possible outcomes of Plasmodium falciparum (P falciparum) malaria infection?
Which factors influence malaria immunity?
How long do Plasmodium species incubate in humans?
What is the life cycle of Plasmodia?
What are the possible sequelae from replication of Plasmodia inside red blood cells (RBCs)?
What is the role of hemozoin in the etiology of malaria?
What is the role of Plasmodia metabolism in the pathophysiology of malaria?
What is the pathogenesis of Plasmodium falciparum (P falciparum) malaria?
What is the pathophysiology of malaria caused by Plasmodium vivax (P vivax)?
What is the pathophysiology of malaria caused by Plasmodium ovale (P ovale)?
What is the disease course of malaria caused by Plasmodium malariae (P malariae)?
What is the disease course of malaria caused by Plasmodium knowlesi (P knowlesi)?
What is the incidence of malaria in the US?
What is the mortality rate for malaria?
What is the global incidence of malaria?
Which malaria comorbidity is associated with a worse prognosis?
How does the incidence of malaria vary between men and women?
Which age group is at an increased mortality risk from malaria?
What is the prognosis of malaria?
What are the possible complications of malaria caused by Plasmodium falciparum (P falciparum)?
What is the mortality rate of malaria?
What are the host protective factors against malaria?
What information about malaria should be given to individuals traveling to endemic regions?
Presentation
What should be the focus of the patient history for suspected malaria?
What is the incubation period for malaria infection and what symptoms occur?
How is the onset of malaria symptoms characterized?
What are less common symptoms of malaria?
What is the presentation of Plasmodium vivax (P vivax) malaria infection?
What is the presentation of Plasmodium malariae (P malariae) malaria infection?
What findings suggest Plasmodium knowlesi (P knowlesi) malaria?
What are the symptoms of malarial infection?
What is the presentation of severe malaria?
What are the symptoms of malaria in children?
What causes anemia in patients with malaria?
What is the treatment of renal failure in patients with severe malaria?
What are the respiratory symptoms of malaria?
DDX
Which conditions should be included in the differential diagnoses of malaria?
Workup
In travelers returning from endemic areas, which findings suggest malaria?
What should be considered in patients who do not respond to antimalarial therapy?
What lab tests are performed in the workup of malaria?
What test must be performed before treating a malaria patient with primaquine?
What is the role of blood glucose testing in the diagnosis and management of malaria?
What are the BCSH recommendations for the lab diagnosis of malaria?
What is the role of imaging studies in the workup of malaria?
What is the role of microhematocrit centrifugation in the workup of malaria?
What is the indication for fluorescent and ultraviolet testing in the workup of malaria?
What is the role of PCR assay testing in the workup of malaria?
What is the role of lumbar puncture in the workup of malaria?
What is the role of blood smears in the workup of malaria?
How are blood smears examined for malaria?
What is the difference between thick and thin blood smears in the workup of malaria?
When should alternative diagnostic methods to blood smears be used in the workup of malaria?
How effective are rapid diagnostic tests (RDT) in the workup of malaria?
What is the role of the quantitative buffy coat (QBC) technique in the diagnosis of malaria?
How should a diagnosis of malaria be reported?
What are the histologic findings for the Plasmodium species associated with malaria?
Treatment
What monitoring is needed of patients treated for malaria?
What may increase the risk of morbidity and mortality in patients with malaria?
What are approach considerations for mixed infections of malaria?
Which Plasmodium species have known resistance to antimalarial agents?
When is inpatient treatment indicated in the treatment of malaria?
What are the increased risks for pregnant women who contract malaria?
How is malaria treated during pregnancy?
What is the disease course of malaria in children?
How is malaria treated in children?
How should diet and activity be modified in patients with malaria?
What are the treatment options for severe complicated malaria?
What is the efficacy of artesunate for the treatment of malaria?
How common is drug resistance in Plasmodium falciparum (P falciparum) malaria?
What is the role of artemisinin in the treatment of malaria?
Is there a vaccine for malaria?
What are the general recommendations for the treatment of malaria?
What is the role of mefloquine hydrochloride for the treatment of malaria?
What is the role of tafenoquine (Krintafel) in preventing malaria relapse?
Which medications are used to treat malaria during pregnancy?
When is inpatient care indicated for the treatment of malaria?
How often should blood smears be obtained during the treatment of malaria?
How much DEET should be used to repel mosquitoes and prevent malaria?
What is the role of chemoprophylaxis in the prevention of malaria?
What progress is being made on the development of a malaria vaccine?
When are specialist consultations needed for the diagnosis and treatment of malaria?
What consultations are needed for the treatment of pregnant patients with malaria?
Medications
Which major drug classes are used to treat malaria?
What is the prevalence of counterfeit antimalarial drugs?
What is the role of antipyretics in the treatment of malaria?
What are the possible adverse effects of antimalarial drugs for the treatment of malaria?
What are the possible complications of high-dose quinine for the treatment of malaria?
Which medications in the drug class Antimalarials are used in the treatment of Malaria?