Continuing Education Activity

Malaria is a potentially life-threatening mosquito-borne infection that remains a major global public health concern and an important diagnosis in febrile travelers returning from endemic regions. Clinical manifestations range from asymptomatic parasitemia to uncomplicated illness and severe disease with cerebral malaria, acidosis, acute kidney injury, pulmonary edema, severe anemia, hypoglycemia, shock, and death. A practice gap persists in clinicians’ ability to consistently recognize travel-related risk, distinguish uncomplicated from severe malaria, initiate urgent diagnostic testing, interpret microscopy and rapid diagnostic test results, select appropriate antimalarial therapy, and provide effective prevention counseling. This activity addresses that gap by reviewing malaria epidemiology, life cycle, pathophysiology, clinical manifestations, diagnostic criteria, treatment strategies, complications, chemoprophylaxis, vaccines, monoclonal antibodies, and interprofessional care. Participants are expected to improve diagnostic accuracy, expedite treatment, prevent complications, and strengthen patient-centered counseling for travelers and high-risk populations.

Objectives:

• Identify epidemiologic, travel-related, pregnancy-related, and immunity-related risk factors associated with uncomplicated and severe malaria.
• Differentiate uncomplicated malaria from severe malaria using clinical findings, laboratory criteria, and patient-specific risk factors.
• Select appropriate antimalarial therapy based on species, disease severity, pregnancy status, drug susceptibility, travel region, and ability to tolerate oral medication.
• Collaborate with the interprofessional healthcare team to coordinate urgent testing, treatment, monitoring, complication recognition, pharmacy support, laboratory reporting, and public health notification for patients with malaria.

Introduction

Malaria is a mosquito-borne disease transmitted by Anopheles species mosquitoes and caused by 6 protozoa: Plasmodium falciparum, P vivax, P malariae, P ovale wallikeri, P ovale curtisi, and P knowlesi.[1] Infection with P falciparum accounts for more than 90% of global malaria mortality and therefore remains an important global public health threat. The 2025 World Malaria Report estimates 282 million cases of malaria worldwide, causing 610,000 deaths, many among children younger than 5 years. [WHO World Malaria Report 2025]. Malaria is endemic in more than 85 countries, mostly tropical or subtropical, affecting approximately 40% of the world’s population. Malaria cases in the US occur almost exclusively among travelers returning from endemic regions, with approximately 2000 cases reported annually from 2007 to 2022, whereas the European Union reported 8000 cases annually from 2018 to 2019. Malaria is associated with travel to endemic areas, and increasing numbers of imported cases necessitate an understanding of nonspecific symptoms, diagnostic challenges, and the urgent treatment of patients with suspected severe malaria.

Etiology

Six species of the genus Plasmodium are known to cause malaria in humans, although worldwide, the vast majority of severe malaria is caused by P falciparum. The vector for Plasmodium spp is a female Anopheles mosquito, which inoculates sporozoites contained in its salivary glands into the puncture wound during feeding (see Image. Mosquito-Borne Diseases).[2] Sporozoites enter the peripheral bloodstream and are taken up by hepatocytes, where they undergo an asexual preerythrocytic liver stage as liver schizonts for up to 2 weeks before the onset of the blood stage.[2][3] During replication within hepatocytes, sporozoites differentiate into motile merozoites, which are subsequently released into the bloodstream, where they invade red blood cells. The process continues through serial cycles of asexual merozoite replication, progressing through ring, trophozoite, and schizont stages before forming and releasing new, invasive daughter merozoites that subsequently infect new red blood cells, thereby increasing parasite numbers.[2][4] 

P falciparum produces high levels of blood-stage parasites and is known to modify the surface of infected red blood cells, creating an adhesive phenotype (ie, sticky cells) that causes red blood cell sequestration in small- and medium-sized vessels and removes the parasite from the circulation for nearly half of the asexual cycle.[5] Sequestration leads to impaired splenic parasite clearance, endothelial damage in host cells, and microvascular obstruction.[4][5] A small fraction of intraerythrocytic parasites switch to sexual development, producing morphologically distinct male and female gametocytes that reach the host's dermis and are ingested by a mosquito, rendering the mosquito infectious to humans (see Image. Plasmodium Life Cycle).[2][3][4] 

After ingestion by a female Anopheles mosquito, the male microgametocytes go through exflagellation in the mosquito's midgut, fusing with female macrogametes to form a zygote. The zygote then develops into an ookinete, which migrates through a thin wall and matures into an oocyst, which produces and, upon rupture, releases numerous sporozoites that are dispersed throughout the mosquito's body, including the salivary glands, thereby completing the life cycle. Gametocytes are therefore of vital importance to the transmission cycle of malaria.[3][6][7] However, the clinical symptoms predominantly result from the asexual stages of parasite replication in human blood.[4] 

P vivax, P ovale curtisi, and P ovale wallikerii may cause relapsing malaria because dormant parasites, called hypnozoites, can activate weeks, months, or years after the initial infection and require specific antimalarial drugs to achieve a radical cure after treatment of the acute disease. The severity of P falciparum infection is mediated by its ability to infect erythrocytes of all ages, which leads to a high parasite burden, and the ability of trophozoite and schizont forms to sequester in the microvasculature rather than be removed from the circulation by the spleen.[8] Adherence of infected erythrocytes to the microvasculature results in pathologies such as cerebral malaria and placental malaria involving the intervillous space, jeopardizing pregnancies.[9]

Epidemiology

Worldwide 

The World Health Organization World Malaria Report 2025 states that an estimated 282 million cases of malaria occurred worldwide in 2024, of which 610,000 were fatal. Sub-Saharan Africa accounts for 95% of global malaria deaths, with approximately 75% of these deaths occurring in children younger than 5 years and almost half occurring in Nigeria, the Democratic Republic of the Congo, and Niger.[WHO. World Malaria Report 2025] 

The United States 

Most malaria cases diagnosed in the US are imported from endemic countries.[10] The risk of infection depends on the length of exposure and the intensity of malaria transmission in the geographical region.[11] During 2022, the Centers for Disease Control and Prevention (CDC) received 1999 reports of confirmed malaria in the US, of which 10 cases were fatal. The majority of US cases (69%) were caused by P falciparum, and 90.2% of the cases were among travelers to Africa.[CDC. Malaria Surveillance, United States, 2022] Based on current climate change projections, researchers expect an expansion in the geographic distribution of malaria and an increasingly suitable climate for malaria transmission in tropical regions.[12] However, several other determinants of the epidemiology of malaria, besides global warming, include war, economic development, urbanization, population growth, and changes in migration.[2][12] Additionally, the impending threat of artemisinin- and multidrug-resistant P falciparum is particularly prevalent in the Greater Mekong Subregion, leading to delayed parasitemia clearance with artemisinin-based combination therapies.[2][13] Thus far, the artemisinin resistance is partial but has been identified through surveillance efforts at low rates in Africa and elsewhere.[WHO. World Malaria Report 2025] 

General Epidemiology and Risk Groups

Severe malaria occurs in patients with little or no effective immunity. In parts of the world with stable and intense transmission of P falciparum, severe malaria primarily affects children younger than 5 years, because specific acquired immunity develops with age through repeated infections, providing increased, although incomplete, protection in older children and adults. However, severe malaria can occur at any age in areas with low or unstable transmission rates and in individuals with no immunity (eg, travelers to endemic areas).[14] 

Susceptibility to severe malaria increases during pregnancy.[15] Pregnant women in the second trimester are at the greatest risk of severe malaria, although the risk is somewhat affected by age and gravidity, with young primigravid patients at the highest risk in high-transmission areas.[16] Women living in areas with unstable and low malaria transmission rates are infected infrequently and therefore lack immunity, which often causes rapid progression to severe malaria and death.[15]

Pathophysiology

The rupture of the first liver schizont and release of motile merozoites into peripheral circulation to invade red blood cells mark the start of a possible symptomatic infection. The first rupture and invasion are usually silent in most infected patients, but parasitemia rises and the immune response increases as the asexual cycle repeats itself during the next 24 to 48 hours. This process is usually associated with increased tumor necrosis factor α levels and other inflammatory markers in the cascade, including IL-10 and interferon-γ.[5] Higher parasitemias are generally associated with a more severe clinical picture, but the relationship is very variable.[17] 

The most important virulence determinant in P falciparum infection is the parasite's ability to modify the surface of the infected red blood cell, thereby creating an adhesive phenotype. Cytoadhesion is mediated through the P falciparum erythrocyte membrane protein 1 (PfEMP1) family, which is the product of var gene transcription. Immense diversity exists in var genes in the parasite population, which has recently been a focus of research, because results from studies suggested an association between increased transcription of specific var genes and the development of severe malaria.[5][18] The cytoadherence of mature-stage infected red blood cells to the endothelium, platelets, and uninfected red blood cells causes sequestration in the microvasculature of various organs, resulting in microcirculation obstruction, impaired tissue perfusion, lactic acidosis, and, consequently, end-organ damage.[19][20][21] Furthermore, sequestration occurs in the placenta during pregnancy, causing low birth weight, maternal anemia, miscarriage, and congenital malaria.[5][20] In essence, the key features that render P falciparum malaria potentially fatal are sequestration of P falciparum in tissues, upregulation of cytokines and other toxic substances, and delayed or absent effective antimalarial therapy.[5]

Histopathology

The histopathologies most commonly associated with severe malaria are hyperparasitemia of greater than 10% infected erythrocytes on blood smear for P falciparum and greater than 100,000 parasites/µL for P knowlesi; however, no cutoff exists for P vivax.[22] In the case of P vivax, parasitemia is usually less than 1%, even when pathology is severe, because much of the P vivax biomass resides in the spleen. P falciparum adheres to the endothelium, causing pathology in the brain, lung, spleen, liver, kidneys, and placenta. P falciparum infection leads to platelet-mediated clumping of erythrocytes and rosetting, which is the binding of infected erythrocytes to uninfected erythrocytes.[23] The WHO uses a criterion of greater than 10% infected erythrocytes on blood smear for P falciparum organisms, whereas the CDC uses a criterion of greater than 5% (see Image. Plasmodium falciparum Gametocyte and Ring-Stage Trophozoites in a Thin Blood Smear).[CDC. Malaria Surveillance, United States, 2022] 

History and Physical

Malaria is a complex disease with a spectrum of clinical effects that not only differ between children and adults but also can range from asymptomatic parasitemia, typically in individuals from endemic regions with a history of repeated infections, to uncomplicated malaria and severe and lethal malaria.[21] The mean incubation period for P falciparum infection is 12 days, with most patients presenting in the first or second month after exposure in endemic areas.[24] A detailed travel history is key in any patient with fever or a history of fever, because malaria is a crucial diagnosis to consider in any individual who has traveled to a malaria-endemic area.[24]

Uncomplicated P falciparum Malaria 

Malaria can be separated into 2 disease presentations: uncomplicated and severe.[3] Uncomplicated malaria is defined by the WHO as the absence of clinical or laboratory signs consistent with severe malaria (see Image. Clinical and Laboratory Diagnostic Criteria for Severe Plasmodium falciparum Malaria).[WHO. World Malaria Report 2025] Symptoms are generally nonspecific, including fever, chills, myalgia, headache, anorexia, and cough, making clinical diagnosis unreliable.[3][25] Patients occasionally present with gastrointestinal, respiratory, and jaundice symptoms.[24] Classic malarial paroxysms with spiking fever, chills, and rigors occurring at specific intervals are relatively uncommon, but if present, they suggest infection with P ovale or P vivax.[2] Progression to severe or ultimately fatal disease is largely confined to P falciparum infections, although only a small percentage of infections progress to severe malaria.[14][21] Features of severe disease usually appear after 3 to 7 days of the above-mentioned nonspecific symptoms, although rapid deterioration, failure to recover consciousness after a generalized tonic-clonic seizure, and death within 24 hours of the first symptom have been reported in patients who are not immune.[14]

Severe P falciparum Malaria

Any patient with P falciparum parasitemia, either detected in the peripheral blood smear or confirmed with a rapid diagnostic test, with no other confirmed cause of symptoms, and who is unable to take oral medications or presents with at least 1 of the clinical or laboratory features listed below, is classified as having severe malaria.[14][26] Although P falciparum is responsible for the majority of severe malaria cases, severe malaria is also observed, although rarely, with P vivax and P knowlesi infections.[14][19] A shortened list of danger signs is used for rapid clinical assessment, including prostration, respiratory distress, acidotic breathing, and impaired consciousness.[27] Other clinical manifestations of severe malaria include multiple convulsions, radiologically confirmed pulmonary edema, respiratory failure due to acute lung injury progressing to acute respiratory distress syndrome, abnormal bleeding, disseminated intravascular coagulation, acute kidney injury, jaundice, pallor, shock, and coma.[3][14][25] Laboratory findings in severe malaria can show severe anemia, hypoglycemia, acidosis, hyperlactatemia, renal impairment, and hyperparasitemia (see Image. Clinical and Laboratory Diagnostic Criteria for Severe Plasmodium falciparum Malaria).[14][19] 

Physical Examination

Physical examination findings are usually unremarkable, especially in patients with uncomplicated malaria. Patients frequently present with irregular and erratic fever, with a temperature of up to 41 °C, sometimes accompanied by agitation or confusion.[2][14] Mild, spontaneously resolving jaundice can sometimes be seen in patients with otherwise uncomplicated P falciparum malaria.[2][24] Other physical signs can include anemia and postural hypotension.[14] In some cases, patients can present with tender hepatosplenomegaly after several days. However, a palpable spleen is particularly common in otherwise healthy populations in endemic areas because of repeated infections (see Image. Clinical and Laboratory Diagnostic Criteria for Severe Plasmodium falciparum Malaria).[2][14][19] 

Children

Children are more likely to present with nonspecific and gastrointestinal tract symptoms such as fever, lethargy, malaise, nausea, vomiting, abdominal cramps, and somnolence.[28] Children are more likely to develop hepatomegaly, splenomegaly, and severe anemia without major organ dysfunction than adults. In severe malaria, children present with more frequent seizures, occurring in 60% to 80%, hypoglycemia, and concomitant sepsis, but are less likely to develop pulmonary edema and renal failure than adults.[2][24] 

Pregnant Women

The clinical features of infection in pregnancy vary from asymptomatic to severe, depending on the degree of incomplete immunity present prior to the pregnancy. Malaria in pregnancy has a devastating effect not only on maternal health but also has been associated with increased infant mortality due to low birth weight caused by either intrauterine growth restriction or preterm labor or both.[16] P falciparum infections are associated with complications such as maternal anemia, low birth weight, miscarriage, stillbirth, and congenital malaria.[5][16] Pregnant patients in the second or third trimester are more likely to develop severe malaria with complications such as hypoglycemia and pulmonary edema, including acute respiratory distress syndrome, compared to nonpregnant adults.[19]

Evaluation

Once malaria is considered a possible diagnosis, laboratory testing must begin immediately.[3] Clinicians must distinguish between nonfalciparum and falciparum malaria.[29] According to the CDC guidelines, malaria should be suspected in any febrile patient with a recent history of travel to endemic areas. The clinical features of either uncomplicated or severe malaria are nonspecific, therefore requiring diagnosis by microscopy or a rapid diagnostic test.[19] The results should be communicated to the requesting clinician urgently, ideally within a few hours.[29]

A complete blood cell count, blood urea nitrogen, creatinine, electrolyte levels, blood glucose, and liver function tests should be performed routinely. Thrombocytopenia suggests either nonfalciparum or falciparum malaria infection in nonimmune adults and children. In severely ill patients, additional studies such as arterial blood gases, blood cultures, lactate levels, and clotting studies are appropriate. After space-occupying brain lesions are excluded in patients with fever and impaired consciousness, clinicians should consider a lumbar puncture to exclude meningitis.[29]

The gold standard for diagnosis is microscopic analysis of thick and thin blood smears (see Image. Plasmodium falciparum Trophozoites in a Peripheral Thin Blood Smear). Thick smears allow sensitive quantification of parasitemia, because parasitemias as low as 30 to 50/µL can be detected. Conversely, thin smears enable determination of the Plasmodium species, prognostic assessment based on the staging of parasite development, and estimation of the proportion of neutrophils containing malaria pigment.[14][19] Three sets of thick and thin blood films spaced 12 to 24 hours apart should be performed by experienced laboratory personnel before a clinician can confidently rule out malaria.[30] 

Perceived peripheral blood parasitemia varies greatly in patients with severe malaria because of sequestration of infected red blood cells in tissues.[14][19] Although severe malaria can present with a low parasite count, high counts are associated with an increased risk of deterioration and subsequent treatment failure even without signs or symptoms of severity.[14] Parasitemia greater than 2% is associated with an increased risk of severe disease, and parasitemia greater than 10% is considered a diagnostic criterion for severe disease and increased mortality.[29] Furthermore, in severe falciparum malaria, poor outcomes can be predicted by the presence of late-stage parasites in red blood cells and more than 5% of neutrophils containing pigment.[19] 

Rapid diagnostic tests are commonly used in addition to blood slides and are useful alternatives in settings where microscopic diagnosis is unreliable or infeasible.[10][UK Health Security Agency. Guidelines for Malaria Prevention in Travelers From the UK 2024] However, all rapid diagnostic tests should be followed by microscopy for confirmation and, if the results are positive, quantification of parasitemia.[10] Rapid diagnostic tests are immunochromatographic tests that most commonly detect either malaria antigens, [eg, P falciparum histidine-rich protein 2 (PfHRP2)], or an enzyme called Plasmodium lactate dehydrogenase (pLDH). These tests have several limitations: they cannot provide quantitative results, can remain positive for months after infection with P falciparum, or, if pLDH results are positive, only while viable parasites remain in the blood.[14] 

Polymerase chain reaction is another diagnostic modality, but it is inadequate for the urgent need to diagnose acute malaria due to its long turnaround time. However, the polymerase chain reaction should be used for research and epidemiologic purposes in any malarial infection in the US to determine and confirm the infecting species.[30] All cases should also be evaluated for evidence of drug resistance, according to CDC guidelines.[10]

Laboratory Diagnostic Criteria for Severe P falciparum, P vivax, and P knowlesi Infection

Severe P vivax malaria is defined the same way as P falciparum malaria, but with no parasite density threshold. Severe P knowlesi malaria is defined the same way as P falciparum malaria, but with 2 differences: hyperparasitemia at parasite density greater than 100,000/µL or jaundice with parasite density greater than 20,000/µL. The WHO uses a criterion of greater than 10% infected erythrocytes on blood smear for P falciparum, whereas the CDC uses a criterion of greater than 5% (see Image. Clinical and Laboratory Diagnostic Criteria for Severe Plasmodium falciparum Malaria).[CDC. Treatment of Severe Malaria] 

Treatment / Management

P falciparum malaria can be rapidly fatal if not diagnosed or treated correctly. In nonendemic countries such as the US, diagnosis can be delayed because malaria has no pathognomonic features, and laboratory staff preparing and examining blood smears may be unfamiliar with this uncommon disease. A life-threatening disease may rapidly follow in a patient who initially appeared well. Therefore, a low threshold for hospitalization is appropriate in nonendemic settings for patients who are at higher risk of severe disease, such as persons with no history of malaria, pregnant women, young children, and all patients with P knowlesi infection.[31] The CDC recommends that if the diagnosis of malaria is suspected but laboratory diagnosis is delayed, treatment for chloroquine-resistant malaria should be initiated immediately. Certainly, when laboratory diagnosis is delayed in a patient with symptoms consistent with severe malaria and strong clinical suspicion plus a convincing exposure history, treatment should be initiated immediately as well.

Treatment should be guided by 3 main factors: the infecting Plasmodium species, the patient's clinical status, and the drug susceptibility of the infecting Plasmodium species, determined by the geographic region where the infection was acquired. Chloroquine sensitivity can be expected if the infection was acquired in Central America west of the Panama Canal, Haiti, or the Dominican Republic. When the diagnosis is strongly suspected but cannot be confirmed, or when species determination is not possible, the clinician should choose a treatment option effective against chloroquine-resistant P falciparum, given the global spread of chloroquine-resistant P falciparum. The CDC recommends making additional blood smears in P falciparum infections after initiating treatment to confirm an adequate parasitological response, including a decrease in parasite density. Malaria acquired from all other geographic regions should be assumed to be chloroquine resistant. Extended, evidence-based, and comprehensive guidelines for malaria treatment and optimal dosing of antimalarial medications are available in the 2025 WHO Guidelines for Malaria.[WHO. WHO Guidelines for Malaria 2025] Treatment algorithms for malaria in the US are available on the CDC official website, as well as recommendations on how to access intravenous artesunate at any time.[CDC. Treatment of Severe Malaria]

Uncomplicated P falciparum Malaria 

Uncomplicated falciparum malaria should be treated with 1 of the artemisinin-based combination therapies (ACTs), such as artemether-lumefantrine. ACTs are highly effective because they result in faster parasite clearance, the paired drugs have complementary action by being longer-acting, and 2-drug regimens reduce the risk of selecting drug resistance; therefore, ACTs are considered the drugs of choice for uncomplicated malaria.[29] The duration of ACT treatment is 3 days. As of 2025, both the WHO and the CDC recommend ACTs for pregnant women in all trimesters. In low-transmission regions such as the Greater Mekong Subregion or Eswatini, where programs aim to eliminate malaria, gametocytocidal therapy (eg, primaquine) is added to ACTs to reduce transmission potential, except in pregnant women, infants younger than 6 months, and women breastfeeding infants younger than 6 months.[19]

Alternative treatment options, although not as effective as ACTs, include atovaquone-proguanil, quinine sulfate plus doxycycline, tetracycline, or clindamycin, and mefloquine. For chloroquine-sensitive P falciparum infections, including infections in pregnant women, the drug of choice is chloroquine or hydroxychloroquine. However, any of the drug choices listed above for chloroquine-resistant strains can be used. Treatment options are the same for children, with doses adjusted by the patient’s weight, except that doxycycline and tetracycline are not recommended.

Severe Malaria (P falciparum or Other Species)

All patients diagnosed with or strongly suspected of having severe malaria should be promptly treated with parenteral antimalarial therapy prior to receiving testing results. Effective, urgent, and appropriate treatment has the greatest impact on prognosis.[29] Intravenous or intramuscular artesunate is the first-line treatment in all patients, including children, lactating women, and pregnant women in all trimesters, worldwide. Artesunate should be used for at least 24 hours and no more than 7 days until oral medication is tolerated.[19] Children weighing less than 20 kg should receive a higher dose (3 mg/kg body weight per dose) of artesunate to ensure the equivalent drug effect. The dose for larger children and adults is 2.4 mg/kg body weight per dose. Three doses of intravenous artesunate should be given: the first immediately, followed by a dose at 12 hours, and another at 24 hours. Children younger than 6 years may receive a single rectal dose of artesunate (10 mg/kg).

Intravenous artesunate was approved by the US Food and Drug Administration in 2020 and is commercially available in the US from Avimas.[CDC. Appendix C: How to Acquire Intravenous artesunate in the US 2024] The hospital pharmacist should call Avimas and can expect a return call in less than 30 minutes. Because severe malaria can progress rapidly, alternative drugs must be used when intravenous or intramuscular artesunate is unavailable. The recommended alternative is artemether in preference to quinine or quinidine. Mefloquine is another alternative, but clindamycin and doxycycline are too slow-acting to be used in the initial treatment of severe malaria. If a patient cannot tolerate oral medications, delivery of antimalarial drugs via a nasogastric tube after administration of an antiemetic should be considered. Intravenous artesunate should be administered until the parasite density is 1% or less and the patient is stable, after which a follow-up course of oral antimalarial treatment should be completed. A full 3-day regimen of ACT is recommended; oral atovaquone-proguanil is an alternative. For a returning traveler, the follow-up antimalarial medication should differ from the prophylaxis medication.[19] 

Patients with falciparum malaria should be admitted to the hospital due to the possibility of deterioration even after effective treatment is initiated. Ideally, a patient with severe malaria should be admitted to an intensive care unit for close monitoring of clinical status, vital signs, consciousness level, and laboratory values.[14][29] Supportive therapy is critical, such as glucose to maintain euglycemia and acetaminophen or ibuprofen for fever control, with individualized fluid treatment, because patients present with variable degrees of hypovolemia, acidosis, and acute kidney failure. Blood transfusion is sometimes indicated in severe anemia. Benzodiazepines or intramuscular paraldehyde may be used for seizure control; however, prophylactic anticonvulsant medications are not recommended for uncomplicated malaria. A lumbar puncture should be performed in patients with meningitis symptoms if they can tolerate the procedure. Empiric antibiotics should be used if there is concern for bacterial coinfection, including during the treatment of shock.[3][19][24] If P vivax species is identified as the cause of severe malaria, primaquine or tafenoquine must follow the treatment regimen to treat the hypnozoite phase of the parasite. Please see StatPearls' companion reference, "Plasmodium vivax Malaria," for further information.

Differential Diagnosis

Other travel-related infections include typhoid, viral hemorrhagic fevers (eg, Ebola and Lassa fever), hepatitis, dengue, yellow fever, enteric fever, avian influenza, severe acute respiratory syndrome coronavirus 2, Middle East respiratory syndrome coronavirus, leptospirosis, African tick fever, meningitis, and encephalitis. Nontropical infections such as bacterial pneumonia, septicemia, and influenza should be excluded.[29][32] Cerebral malaria can mimic bacterial meningitis, measles, locally prevalent viral encephalitis, toxic syndromes, and intracranial vascular events.[14]

Toxicity and Adverse Effect Management

Please refer to the StatPearls companion resource, “Antimalarial Medications,” for the potential adverse effects of these drugs.

Prognosis

With timely diagnosis, treatment, and adherence, patients with uncomplicated malaria usually recover without sequelae. The mortality rate rises steeply once the patient develops signs and symptoms of severe malaria, particularly in the case of P falciparum infection. Adults have higher mortality rates and more frequent multisystem involvement than children, with mortality rates of 18.5% and 9.7%, respectively.[21] Results from studies found that the 2 main determinants of outcomes for both adults and children are the level of consciousness assessed by coma scales and the degree of metabolic acidosis, assessed clinically by breathing pattern or, more precisely, by measurement of bicarbonate levels, base deficit, and plasma lactate levels.[14] Although the general mortality rate of treated severe malaria is between 10% and 20%, the mortality rate in pregnant women reaches approximately 50%.[19]

Complications

A distinct complication of P falciparum malaria is cerebral malaria, a diffuse and symmetric encephalopathy.[17] Cerebral malaria is a clinical syndrome defined as impaired consciousness that cannot be attributed to other causes, such as convulsions, hypoglycemia, sedative drugs, or other nonmalarial causes, and is associated with an unequivocal diagnosis of malarial infection (see Image. Clinical and Laboratory Diagnostic Criteria for Severe Plasmodium falciparum Malaria). Because several other possible causes of altered consciousness exist, the presence of retinopathy has been used in an attempt to increase the specificity of the diagnosis of cerebral malaria and improve the classification of severe malaria.[14] Other possible complications, predominantly caused by P falciparum, include:

• Acute kidney injury complicates up to 40% of P falciparum malaria [19]
• Noncardiogenic pulmonary edema, acute respiratory distress syndrome, and hypoxia [14]
• Electrolyte and fluid abnormalities [14]
• Acid-base disturbances, mostly acidosis and hyperlactatemia [14]
• Hypoglycemia, often exacerbated by quinine therapy [3]
• Anemia, with the reduction in hemoglobin levels proportional to disease severity and duration of illness before treatment [14][17]
• Other hematological complications, including delayed hemolytic anemia following artemisinin treatment, hyperreactive malarial splenomegaly, and splenic rupture [3]
• Blackwater fever and hemoglobinuria due to intravascular hemolysis in patients with severe clinical manifestations of falciparum malaria [14]
• Profound thrombocytopenia is often associated with P falciparum infection; however, bleeding and disseminated intravascular coagulation are rare [14]
• Jaundice and hepatic dysfunction [14]
• Shock and associated infections, such as Salmonella bacteremia, aspiration pneumonia, and nosocomial infections [2][14]
• Neurological sequelae, including epilepsy and permanent focal deficits [3]

The 3 most common complications in children are cerebral malaria, severe anemia, and acidosis, either isolated or overlapping; in adults, vital organ dysfunction, acidosis, and renal failure are poor prognostic factors.[21] 

Deterrence and Patient Education

Although no intervention for preventing malaria infection is 100% effective, several different approaches are available and can be used alone or in combination. Personal protective measures reduce the risk of exposure to mosquito vector species, and chemoprophylaxis can prevent malaria.[33] A common approach uses the ABCD of malaria, with A standing for awareness of the risk, B for bite avoidance, C for compliance with chemoprophylaxis, and D for diagnosis in case of fever. Clinicians should consider the traveler's health, especially pregnancy, age, and immunosuppression, when assessing the risk of developing severe malaria and choosing an appropriate antimalarial drug.[11]

Clinicians should emphasize the importance of personal protective measures such as barrier clothing, insecticide-impregnated bed nets, the application of an effective mosquito repellent, a higher percentage of active ingredient providing longer protection, and spraying the residence with insecticide. Products that contain 20% to 40% DEET (N, N-diethyl-meta-toluamide), picaridin, oil of lemon eucalyptus, PMD (p-menthane-3,8-diol), or IR3535 are recommended. Behaviors to minimize exposure to mosquitoes are also encouraged, including staying indoors from dusk to dawn and choosing screened accommodations.[10][33] Indoor residual spraying and long-lasting insecticidal nets remain the most effective tools for malaria control and elimination, despite the emergence of insecticide-resistant Anopheles mosquitoes.[34]

A standard recommendation for all travelers to endemic areas is strict compliance with antimalarial prophylaxis. Several different drug choices are available and should be prescribed after assessing an individual's risk, including level of local transmission, duration of exposure, rural versus urban travel, type of travel, and season; the traveler's health status; present contraindications; level of parasite drug resistance, mostly chloroquine and mefloquine resistance; and the traveler’s preference based on schedule, cost, and potential adverse effects. Counterfeit and substandard medications are an increasing problem in many countries, and travelers should be advised to buy the needed medications before departure.[11][35] A complete list of drug recommendations is available on the CDC's website.[CDC. Choosing a Drug to Prevent Malaria] Because pregnant women are at increased risk of severe malaria, the WHO and other organizations recommend avoiding travel to endemic areas during pregnancy.[11]

According to the US Food and Drug Administration recommendations, travelers to endemic areas, former residents of malaria-endemic areas, and people diagnosed with malaria should be informed that they may not donate blood for 1 year after travel, 3 years after departing or revisiting the country, or 3 years after treatment, respectively.[FDA. Recommendations to Reduce the Risk of Transfusion-Transmission Malaria 2022] Travelers should be informed that malaria can be fatal with delayed treatment. Therefore, travelers should seek medical attention while abroad if malaria symptoms develop and should not fly back for treatment, as medical care may not be readily available during transit.[10]

Pearls and Other Issues

Vaccines and Monoclonal Antibodies

The identification and development of durable immunity against malaria have long been subjects of research. Vaccine development has been challenging because of the complex life cycle of Plasmodium species and their antigenic variability. In 2021 and 2023, respectively, the WHO recommended the RTS, S/AS01 and R21 vaccines for malaria prevention in children living in malaria-endemic areas. These vaccines are administered in a 4-dose series beginning at approximately 5 months of age.[WHO. WHO Recommends R21/Matrix-M Vaccine for Malaria Prevention in Updated Advice on Immunization]

During clinical trials, these vaccines reduced malaria cases by more than 50% and by up to 75% when administered seasonally in areas with highly seasonal transmission.[36] Vaccine effectiveness may decline over time, particularly in highly endemic regions.[37] The vaccines are currently being introduced in 24 African countries to reach 10 million young children by 2025.[WHO. Malaria Vaccines (RTS,S and R21)]. Neither the FDA nor the European Medicines Agency is considering these vaccines for routine use in adult travelers. Current travel health guidance continues to emphasize chemoprophylaxis and mosquito bite prevention rather than vaccination for short-term travelers.

Subcutaneously administered monoclonal antibodies with extended half-lives have demonstrated efficacy against P falciparum infection. Both L9LS and CIS43LS monoclonal antibodies target antigens of the P falciparum circumsporozoite protein. These agents have shown high levels of protection for several months in results from human challenge studies and in trials involving children and adults living in endemic regions.[38][39][40] Further development is ongoing, and these monoclonal antibodies may become commercially available in the future.

Countering Pyrethroid-Resistant Mosquitoes With Bednets

The emergence of pyrethroid-resistant malaria vector populations has resulted in the deployment of combination insecticidal nets treated with piperonyl butoxide and pyrethroid-treated nets.[34] Dual pyrethroid-chlorfenapyr and pyrethroid-pyriproxyfen insecticide-treated bed nets are also recommended by the WHO.[WHO, WHO Guidelines for Malaria 2025]

Enhancing Healthcare Team Outcomes

Most cases of malaria in the US are imported and could, therefore, be avoided with appropriate personal protective measures and adherence to prescribed chemoprophylaxis. Healthcare professionals at all levels must be educated not only in the diagnosis and treatment of malaria but also in the importance of prevention. Healthcare professionals should be able to provide sufficient information to travelers at risk. Travelers to endemic areas should obtain appropriate clothing, insecticides, bed nets, and other protective gear based on information from healthcare professionals and the CDC. Collaboratively, a clinician and a pharmacist should decide on and recommend appropriate chemoprophylaxis, considering the traveler's personal preferences, season of travel, current health status, risk factors for severe malaria, drug-drug interactions, and possible contraindications, while emphasizing the importance of compliance with the medication regimen.

The crucial issue in the diagnosis and treatment of malaria is the consideration of the possibility of malaria in a febrile returned traveler. Expert advice from an infectious disease or travel medicine specialist should be sought once malaria is suspected, especially in the setting of severe disease.[29] Microscopic analysis of a stained blood smear often depends on several factors, including laboratory equipment, reagent quality, and laboratory expertise. Therefore, laboratory personnel should be trained in the preparation and analysis of blood smears to correctly diagnose malaria infection. The results need to be communicated to the clinician urgently. All laboratory-confirmed cases of malaria should be reported to the CDC to help with surveillance efforts. Healthcare professionals on the interprofessional team, including nurses, respiratory therapists, and clinicians, who treat patients with severe malaria in critical or intensive care units, should be educated in the early recognition of complications.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Garrido-Cardenas JA, González-Cerón L, Manzano-Agugliaro F, Mesa-Valle C. Plasmodium genomics: an approach for learning about and ending human malaria. Parasitol Res. 2019 Jan;118(1):1-27. [PubMed: 30402656]

2.

Breman JG. Eradicating malaria. Sci Prog. 2009;92(Pt 1):1-38. [PMC free article: PMC10361125] [PubMed: 19544698]

3.

Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Lancet. 2018 Apr 21;391(10130):1608-1621. [PubMed: 29631781]

4.

Meibalan E, Marti M. Biology of Malaria Transmission. Cold Spring Harb Perspect Med. 2017 Mar 01;7(3) [PMC free article: PMC5334247] [PubMed: 27836912]

5.

Milner DA. Malaria Pathogenesis. Cold Spring Harb Perspect Med. 2018 Jan 02;8(1) [PMC free article: PMC5749143] [PubMed: 28533315]

6.

Garcia LS. Malaria. Clin Lab Med. 2010 Mar;30(1):93-129. [PubMed: 20513543]

7.

Drakeley C, Sutherland C, Bousema JT, Sauerwein RW, Targett GA. The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion. Trends Parasitol. 2006 Sep;22(9):424-30. [PubMed: 16846756]

8.

Simpson JA, Silamut K, Chotivanich K, Pukrittayakamee S, White NJ. Red cell selectivity in malaria: a study of multiple-infected erythrocytes. Trans R Soc Trop Med Hyg. 1999 Mar-Apr;93(2):165-8. [PubMed: 10450440]

9.

Chua CLL, Khoo SKM, Ong JLE, Ramireddi GK, Yeo TW, Teo A. Malaria in Pregnancy: From Placental Infection to Its Abnormal Development and Damage. Front Microbiol. 2021;12:777343. [PMC free article: PMC8636035] [PubMed: 34867919]

10.

Gerstenlauer C. Recognition and Management of Malaria. Nurs Clin North Am. 2019 Jun;54(2):245-260. [PubMed: 31027664]

11.

Genton B, D'Acremont V. Malaria prevention in travelers. Infect Dis Clin North Am. 2012 Sep;26(3):637-54. [PubMed: 22963775]

12.

Cella W, Baia-da-Silva DC, Melo GC, Tadei WP, Sampaio VS, Pimenta P, Lacerda MVG, Monteiro WM. Do climate changes alter the distribution and transmission of malaria? Evidence assessment and recommendations for future studies. Rev Soc Bras Med Trop. 2019;52:e20190308. [PubMed: 31800921]

13.

Dondorp AM, Smithuis FM, Woodrow C, Seidlein LV. How to Contain Artemisinin- and Multidrug-Resistant Falciparum Malaria. Trends Parasitol. 2017 May;33(5):353-363. [PubMed: 28187990]

14.

Severe malaria. Trop Med Int Health. 2014 Sep;19 Suppl 1:7-131. [PubMed: 25214480]

15.

Fried M, Duffy PE. Malaria during Pregnancy. Cold Spring Harb Perspect Med. 2017 Jun 01;7(6) [PMC free article: PMC5453384] [PubMed: 28213434]

16.

Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007 Feb;7(2):93-104. [PubMed: 17251080]

17.

White NJ. Anaemia and malaria. Malar J. 2018 Oct 19;17(1):371. [PMC free article: PMC6194647] [PubMed: 30340592]

18.

Duffy F, Bernabeu M, Babar PH, Kessler A, Wang CW, Vaz M, Chery L, Mandala WL, Rogerson SJ, Taylor TE, Seydel KB, Lavstsen T, Gomes E, Kim K, Lusingu J, Rathod PK, Aitchison JD, Smith JD. Meta-analysis of Plasmodium falciparum var Signatures Contributing to Severe Malaria in African Children and Indian Adults. mBio. 2019 Apr 30;10(2) [PMC free article: PMC6495371] [PubMed: 31040236]

19.

Plewes K, Leopold SJ, Kingston HWF, Dondorp AM. Malaria: What's New in the Management of Malaria? Infect Dis Clin North Am. 2019 Mar;33(1):39-60. [PubMed: 30712767]

20.

Beeson JG, Brown GV. Pathogenesis of Plasmodium falciparum malaria: the roles of parasite adhesion and antigenic variation. Cell Mol Life Sci. 2002 Feb;59(2):258-71. [PMC free article: PMC11146193] [PubMed: 11915943]

21.

Wassmer SC, Taylor TE, Rathod PK, Mishra SK, Mohanty S, Arevalo-Herrera M, Duraisingh MT, Smith JD. Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach. Am J Trop Med Hyg. 2015 Sep;93(3 Suppl):42-56. [PMC free article: PMC4574273] [PubMed: 26259939]

22.

Daily JP, Minuti A, Khan N. Diagnosis, Treatment, and Prevention of Malaria in the US: A Review. JAMA. 2022 Aug 02;328(5):460-471. [PubMed: 35916842]

23.

Banda JP, Walker IS, Nyirenda T, Aitken EH, Rogerson SJ. Breaking the bind: PfEMP1-specific antibodies in cerebral malaria. Front Immunol. 2025;16:1681852. [PMC free article: PMC12611861] [PubMed: 41246335]

24.

Fletcher TE, Beeching NJ. Malaria. J R Army Med Corps. 2013 Sep;159(3):158-66. [PubMed: 24109136]

25.

Silva GBD, Pinto JR, Barros EJG, Farias GMN, Daher EF. Kidney involvement in malaria: an update. Rev Inst Med Trop Sao Paulo. 2017;59:e53. [PMC free article: PMC5626226] [PubMed: 28793022]

26.

Sypniewska P, Duda JF, Locatelli I, Althaus CR, Althaus F, Genton B. Clinical and laboratory predictors of death in African children with features of severe malaria: a systematic review and meta-analysis. BMC Med. 2017 Aug 03;15(1):147. [PMC free article: PMC5541406] [PubMed: 28768513]

27.

Daily JP, Parikh S. Malaria. N Engl J Med. 2025 Apr 03;392(13):1320-1333. [PMC free article: PMC12331251] [PubMed: 40174226]

28.

Friedman-Klabanoff DJ, Adu-Gyasi D, Asante KP. Malaria prevention in children: an update. Curr Opin Pediatr. 2024 Apr 01;36(2):164-170. [PMC free article: PMC10932812] [PubMed: 38299986]

29.

Lalloo DG, Shingadia D, Bell DJ, Beeching NJ, Whitty CJM, Chiodini PL., PHE Advisory Committee on Malaria Prevention in UK Travellers. UK malaria treatment guidelines 2016. J Infect. 2016 Jun;72(6):635-649. [PMC free article: PMC7132403] [PubMed: 26880088]

30.

Mace KE, Arguin PM, Tan KR. Malaria Surveillance - United States, 2015. MMWR Surveill Summ. 2018 May 04;67(7):1-28. [PMC free article: PMC5933858] [PubMed: 29723168]

31.

Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008 Jan 15;46(2):165-71. [PMC free article: PMC2533694] [PubMed: 18171245]

32.

Scaggs Huang FA, Schlaudecker E. Fever in the Returning Traveler. Infect Dis Clin North Am. 2018 Mar;32(1):163-188. [PMC free article: PMC7135112] [PubMed: 29406974]

33.

Chen LH, Wilson ME, Schlagenhauf P. Prevention of malaria in long-term travelers. JAMA. 2006 Nov 08;296(18):2234-44. [PubMed: 17090770]

34.

Killeen GF, Ranson H. Insecticide-resistant malaria vectors must be tackled. Lancet. 2018 Apr 21;391(10130):1551-1552. [PubMed: 29655495]

35.

Brower V. Counterfeit and substandard malaria drugs in Africa. Lancet Infect Dis. 2017 Oct;17(10):1026-1027. [PubMed: 28948928]

36.

Datoo MS, Dicko A, Tinto H, Ouédraogo JB, Hamaluba M, Olotu A, Beaumont E, Ramos Lopez F, Natama HM, Weston S, Chemba M, Compaore YD, Issiaka D, Salou D, Some AM, Omenda S, Lawrie A, Bejon P, Rao H, Chandramohan D, Roberts R, Bharati S, Stockdale L, Gairola S, Greenwood BM, Ewer KJ, Bradley J, Kulkarni PS, Shaligram U, Hill AVS., R21/Matrix-M Phase 3 Trial Group. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet. 2024 Feb 10;403(10426):533-544. [PMC free article: PMC7618965] [PubMed: 38310910]

37.

Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, Kaslow DC, Njuguna P, Marsh K, Bejon P. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children. N Engl J Med. 2016 Jun 30;374(26):2519-29. [PMC free article: PMC4962898] [PubMed: 27355532]

38.

Wu RL, Idris AH, Berkowitz NM, Happe M, Gaudinski MR, Buettner C, Strom L, Awan SF, Holman LA, Mendoza F, Gordon IJ, Hu Z, Campos Chagas A, Wang LT, Da Silva Pereira L, Francica JR, Kisalu NK, Flynn BJ, Shi W, Kong WP, O'Connell S, Plummer SH, Beck A, McDermott A, Narpala SR, Serebryannyy L, Castro M, Silva R, Imam M, Pittman I, Hickman SP, McDougal AJ, Lukoskie AE, Murphy JR, Gall JG, Carlton K, Morgan P, Seo E, Stein JA, Vazquez S, Telscher S, Capparelli EV, Coates EE, Mascola JR, Ledgerwood JE, Dropulic LK, Seder RA., VRC 614 Study Team. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria. N Engl J Med. 2022 Aug 04;387(5):397-407. [PMC free article: PMC9806693] [PubMed: 35921449]

39.

Kayentao K, Ongoiba A, Preston AC, Healy SA, Hu Z, Skinner J, Doumbo S, Wang J, Cisse H, Doumtabe D, Traore A, Traore H, Djiguiba A, Li S, Peterson ME, Telscher S, Idris AH, Adams WC, McDermott AB, Narpala S, Lin BC, Serebryannyy L, Hickman SP, McDougal AJ, Vazquez S, Reiber M, Stein JA, Gall JG, Carlton K, Schwabl P, Traore S, Keita M, Zéguimé A, Ouattara A, Doucoure M, Dolo A, Murphy SC, Neafsey DE, Portugal S, Djimdé A, Traore B, Seder RA, Crompton PD., Mali Malaria mAb Trial Team. Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria. N Engl J Med. 2024 May 02;390(17):1549-1559. [PMC free article: PMC11238904] [PubMed: 38669354]

40.

Kayentao K, Ongoiba A, Preston AC, Healy SA, Doumbo S, Doumtabe D, Traore A, Traore H, Djiguiba A, Li S, Peterson ME, Telscher S, Idris AH, Kisalu NK, Carlton K, Serebryannyy L, Narpala S, McDermott AB, Gaudinski M, Traore S, Cisse H, Keita M, Skinner J, Hu Z, Zéguimé A, Ouattara A, Doucoure M, Dolo A, Djimdé A, Traore B, Seder RA, Crompton PD., Mali Malaria mAb Trial Team. Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali. N Engl J Med. 2022 Nov 17;387(20):1833-1842. [PMC free article: PMC9881676] [PubMed: 36317783]

Disclosure: Taraz Samandari declares no relevant financial relationships with ineligible companies.

Disclosure: Erin Gillespie declares no relevant financial relationships with ineligible companies.