Malaria is a complex disease with a spectrum of clinical effects that not only differ between children and adults but can range from practically none in patients with asymptomatic parasitemia, to uncomplicated malaria, through to severe and possibly lethal malaria.[20] The mean incubation period for P. falciparum is 12 days, with most patients presenting in the first or second month after exposure in endemic areas.[21][22] It is key to take a detailed travel history in any patient with fever or history of fever, as malaria is a crucial diagnosis to consider in any individual who has traveled to a malaria-endemic area.[22][21]

Uncomplicated P. falciparum Malaria 

Malaria can be separated into two disease presentations: uncomplicated and severe. [4] The WHO defines the presence of symptoms without clinical or laboratory signs to indicate severity or vital organ dysfunction as uncomplicated malaria.[6] Symptoms are generally non-specific, including fever, chills, myalgia, headache, anorexia, and cough, making clinical diagnosis unreliable.[4][21] Patients occasionally present with gastrointestinal symptoms, respiratory symptoms, and jaundice.[22] The classical malarial paroxysms with spiking fever, chills, and rigors occurring at specific intervals are relatively uncommon, but if present, indicate an infection with P. ovale or P. vivax.[3] Progression to severe or ultimately fatal disease is largely confined to P. falciparum infections, although only a small percentage, approximately 1% to 2% of infections, lead to severe malaria.[20][13] Features of a severe disease usually appear after 3 to 7 days of the abovementioned non-specific symptoms, although there are some reports of rapid deterioration, failure to recover consciousness after a grand-mal seizure, and non-immune patients dying within 24 hours of their first symptom.[13]

Severe P. falciparum Malaria

The patient presenting with at least one of the clinical or laboratory features listed below, with asexual P. falciparum parasitemia (either detected in the peripheral blood smear or confirmed with rapid diagnostic test) and no other confirmed cause of his symptoms, classifies as suffering from severe malaria.[13][23] Although P. falciparum is responsible for the majority of the cases of severe malaria, it is also, albeit rarely, observed with P. vivax and P. knowlesi infections.[18][13]

A shortened list of danger signs is used for rapid clinical assessment, which includes prostration, respiratory distress (acidotic breathing), and impaired consciousness.[4] 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, shock, and coma.[4][21][13] Laboratory features in severe malaria can show severe anemia, hypoglycemia, acidosis, hyperlactatemia, renal impairment, and hyperparasitemia.[13] A comprehensive list of diagnostic criteria for falciparum malaria is shown in Table 1 - Diagnostic criteria for severe P. falciparum malaria.[13][18]

Physical Examination

Physical examination is usually unremarkable, especially of patients with uncomplicated malaria. They frequently present with irregular and erratic fever, reaching up to 41°C, sometimes accompanied by agitation or confusion.[3][13] Mild spontaneously resolving jaundice can sometimes be seen in patients with otherwise-uncomplicated falciparum malaria. [3][22] Other physical signs can include anemia and postural hypotension.[13] In some cases, patients can present with tender hepatosplenomegaly after some days. However, a palpable spleen is particularly common in otherwise healthy populations in endemic areas, reflecting repeated infections.[3] The comprehensive list of clinical features associated with severe malaria is shown in Table 1 - Diagnostic criteria for severe P. falciparum malaria.[13][18] 

Children

Children are more likely to present with non-specific and gastrointestinal symptoms such as fever, lethargy, malaise, nausea, vomiting, abdominal cramps, and somnolence.[22] They are more likely to develop hepatomegaly, splenomegaly, and severe anemia without major organ dysfunction than adults. In a case of severe malaria, they present with more frequent seizures (in 60% to 80%), hypoglycemia, and concomitant sepsis but are less likely to develop pulmonary edema and renal failure than adults.[3][22] 

Pregnant Women

The clinical features of infection in pregnancy vary from asymptomatic to severe, depending on the degree of (incomplete) immunity that a woman had acquired by the time she got pregnant. In semi-immune pregnant women, only a few infections result in fever or other symptoms.[15] Malaria in pregnancy has a devastating effect not only on maternal health but has been associated with increased infant mortality due to low birth weight caused by either intrauterine growth restriction or preterm labor or both.[15] P. falciparum infections are proven to be associated with complications such as maternal anemia, low birth weight, miscarriage, stillbirths, and congenital malaria.[6][15] It is more likely for a pregnant woman in the second or third trimester to develop severe malaria with complications such as hypoglycemia and pulmonary edema, compared to non-pregnant adults.[18]

Once malaria is considered a possible diagnosis, it is important to facilitate immediate laboratory testing.[4] It is essential to distinguish between non-falciparum and falciparum malaria.[24] As per the Centers for Disease Control and Prevention (CDC) guidelines, malaria should be routinely suspected in any febrile patient that has a recent history of travel to the endemic areas. The clinical features of either uncomplicated or severe malaria are non-specific, therefore requiring diagnosis by microscopy or rapid diagnostic test (RDT).[18] The results should be communicated back to the requesting doctor as soon as possible, ideally within a few hours.[24]

A full blood count, urea, creatinine and electrolytes, blood glucose level, and liver function tests should be routinely performed. Thrombocytopenia suggests both non-falciparum and falciparum malaria infections in non-immune adults and children. In severely ill patients, additional studies such as blood gases, blood culture, lactate, and clotting studies are appropriate. In patients with fever and impaired consciousness, one should consider a lumbar puncture to exclude meningitis.[24]

The golden standard for diagnosis is a microscopic analysis of thick and thin blood smears. Thick smears allow for a sensitive parasitemia quantification, as parasitemias as low as 30-50/microL can be detected, while thin smears enable a determination of the Plasmodium species, prognostic assessment based on the staging of parasite development and estimation of the proportion of neutrophils containing malaria pigment.[13][18] 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.[8] 

Perceived peripheral blood parasitemia varies greatly in patients with severe malaria, due to the sequestration of the infected red blood cells in tissues.[13][18] Although severe malaria can present with low parasite count, high counts are associated with increased risk of deterioration and subsequent treatment failure even without signs or symptoms of severity.[13] More than 2% of parasitized RBC suggests an increased chance of developing severe disease, and parasitemia over 10% is considered as one of the diagnostic criteria for severe disease and is associated with increased mortality.[24] Furthermore, in severe falciparum malaria, poor outcomes can be predicted by the presence of late-stage parasites in RBC and more than 5% of the neutrophils containing pigment.[18] 

Rapid diagnostic tests are commonly used in addition to blood slides and are useful alternatives in settings where a microscopic diagnosis is non-reliable or infeasible.[24][9] It is, however, recommended that all the RDTs should be followed by microscopy for confirmation and, if positive, quantification of parasitemia.[9] They are immune-chromatographic tests that most commonly identify either malaria antigens (e.g., P. falciparum histidine-rich-protein 2 (PfHRP2)) or enzyme called Plasmodium lactate dehydrogenase (pLDH). Tests have several downfalls as they cannot provide quantitative results, can stay positive months after infection with P. falciparum, or are, if testing for pLDH, positive only while there are living parasites in the blood.[13] 

Polymerase chain reaction (PCR) is one of the possible diagnostic modalities but is, even if promptly available, too timely to use for initial diagnosis and prompt treatment of acute malaria. It should, however, be used for research and epidemiologic purposes in any malaria infection in the USA, to determine and confirm the infecting species.[8] All cases should also be evaluated for evidence of drug resistance, as per CDC guidelines.[9]

CDC recommends that the treatment of malaria should not be initiated until the diagnosis has been confirmed by laboratory testing. Treatment should be initiated immediately after the confirmation of malaria infection. Empirical treatment is, however, reserved only for extreme cases where there is a strong clinical suspicion with convincing exposure history, presence of severe disease, or an inability to diagnose malaria due to inadequate laboratory facilities.

The treatment should be guided by three main factors: the infecting Plasmodium species, the clinical status of the patient, and drug susceptibility of infecting Plasmodium, 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 Panama Canal, Haiti, and the Dominican Republic. In a case when the diagnosis is strongly suspected, and it cannot be confirmed, or when there is no species determination possible, given the global spread of P. falciparum resistant to chloroquine, the clinician should opt for a treatment option effective against chloroquine-resistant P. falciparum. CDC recommends making additional blood smears in infections with P. falciparum after initiating the treatment, to confirm adequate parasitological response (decrease in density) to treatment.

Extended, evidence-based, and comprehensive guidelines for malaria management and optimal dosing of antimalarial medications can be found in the third edition of WHOs Guidelines for the treatment of malaria. Treatment and management algorithms for malaria in the USA are available on the CDC´s official website.

Uncomplicated Falciparum Malaria 

Uncomplicated falciparum malaria should be treated with one of the artemisinin-based combination therapies (ACT). Artemisinin-based combination therapy (ACT) is highly effective due to its effect on a broader range of parasite life cycles, causing faster parasite clearance and is therefore considered a drug of choice for uncomplicated malaria.[24] The duration of ACT treatment is 3 days. ACTs are also recommended for pregnant women in the second and third trimester but should be used during the first trimester only if other treatment options are not available. During the first trimester, a combination of quinine and clindamycin should be prescribed. In low transmission areas, gametocytocidal therapy (e.g., primaquine) is added to ACTs to reduce transmission potential (except pregnant women, infants younger than 6 months and women breastfeeding infants younger than 6 months).[18]

There are some other treatment options, although not as effective as ACTs, such as atovaquone-proguanil, quinine sulfate plus doxycycline, tetracycline, or clindamycin, and mefloquine. For chloroquine-sensitive P. falciparum infections (including

pregnant women), the drug of choice is chloroquine. However, any of the drug choices listed above for chloroquine-resistant strains can be used. Treatment options are the same for the pediatric population, with doses adjusted by the patient’s weight. 

Severe Falciparum Malaria

All patients diagnosed or with a strong suspicion with signs and symptoms of severe malaria should be promptly treated with parenteral antimalarial therapy. Effective, urgent, and appropriate treatment has the greatest impact on prognosis.[24] 

Intravenous or intramuscular artesunate is the first-line treatment in all patients (including children, lactating women, and pregnant women in all trimesters) worldwide and should be used for at least 24 hours and until the oral medication is tolerated.[18] Children should receive a higher dose (3 mg/kg BW per dose) of the artesunate to ensure the equivalent drug effect. The dose for larger children and adults is 2.4 mg/kg BW per dose. Three doses of intravenous artesunate should be given: one immediately, followed by a dose at 12 hours and 24 hours.   

If artesunate is not available, the recommended drug is artemether in preference to quinine. After the complete course of a 24 hour intravenous artesunate, a regimen of a follow-up drug should be completed. A full 3-day regimen of ACT is recommended. In returning traveler, the follow-on antimalarial medication needs to be other than the antimalarial medication taken for prophylaxis.[18] 

Intravenous artesunate is currently not approved by the Food and Drug Administration (FDA) or commercially available in the U.S. but is available from CDC under an expanded-access investigational drug (IND) protocol. It is prepositioned at distribution sites throughout the USA and readily available after contacting CDC. Since severe malaria can progress rapidly, CDC offers guidance on oral treatment that can be used while waiting for IV artesunate to be delivered. They recommend interim treatment with oral artemether-lumefantrine (preferably), atovaquone-proguanil, quinine sulfate, or mefloquine. If a patient can not tolerate oral medications, administration after an antiemetic or via nasogastric tube should be considered.

Patients with falciparum malaria should be admitted to the hospital due to the possibility of deterioration even after the effective treatment was initiated. If patients are determined to have uncomplicated malaria, they can be treated as outpatients after confirming that they can tolerate oral therapy, and the parasitemia has declined.[13] Ideally, a patient with severe malaria should be admitted to an intensive-care unit or high dependency unit with close monitoring of clinical status, vital signs, consciousness level, and laboratory values.[13][24]

It is important to provide supportive therapy, such as glucose to maintain euglycemia and acetaminophen for fever control, careful, individualized fluid management as patients present with variable degrees of hypovolemia, acidosis, and acute kidney failure. Blood transfusion is sometimes indicated in severe anemias; benzodiazepines should be used for seizure control. However, prophylactic antiepileptic medications are not recommended, and empiric antibiotics should be used in children with severe malaria and adults with concurrent shock.[4][22][18]

Other travel-related infections such as typhoid, viral hemorrhagic fevers (such as Ebola, Lassa fever, etc.), hepatitis, dengue, and other arboviruses, enteric fever, avian influenza, tuberculosis, MERS-CoV infections, HIV, meningitis, and encephalitis can resemble malaria. Non-tropical infections such as bacterial pneumonia, septicemia, and influenza should be excluded.[24][25]

Cerebral malaria can mimic bacterial meningitis, measles, (locally prevalent) viral encephalitis, toxic syndromes, and intracranial vascular or mechanical events.[13]

Patients with uncomplicated malaria, especially with timely diagnosis, treatment, and proper compliance, usually recover from malaria without consequences. The mortality rate for uncomplicated malaria is low, around 0.1%.[3][6] The mortality rate rises steeply once the patient develops signs and symptoms of severe falciparum malaria. Adults have higher mortality rates and more frequent multisystem involvement than children, with mortality rates being 18.5% and 9.7%, respectively.[20] The two main determinants reflecting the outcome for both adults and children were found to be the level of consciousness assessed by coma scales and the degree of metabolic acidosis, assessed clinically by breathing pattern or more precisely with measurement of bicarbonate, base deficit, and plasma lactate.[13] While the general mortality of treated severe malaria is between 10% to 20%, the mortality in pregnant women reaches approximately 50%.[18]

A distinct complication of P. falciparum malaria is cerebral malaria (CM), a diffuse and symmetrical encephalopathy.[16] It is a clinical syndrome defined as an impaired consciousness (clinically determined as stated in Table 1) that cannot be attributed to other causes such as convulsions, hypoglycemia, sedative drugs, or other non-malarial causes and is associated with an unequivocal diagnosis of malarial infection. Due to several other possible causes of altered consciousness, the presence of retinopathy has been used in an attempt to increase the specificity of diagnosis of CM and improve the classification of severe malaria.[13]

Other possible complications, predominantly caused by P. falciparum, include:

• Acute kidney injury complicates up to 40% of P. falciparum malaria.[18]
• Non-cardiogenic pulmonary edema, acute respiratory distress syndrome (ARDS), and hypoxia[13]
• Electrolyte and fluid abnormalities[13]
• Acid-base disturbances – mostly acidosis and hyperlactatemia[13]
• Hypoglycemia, often exacerbated by quinine therapy[4]
• Anemia, with the reduction in hemoglobin levels being proportional to disease severity and duration of illness before treatment[13][16]
• Other hematological complications (delayed hemolytic anemia following artemisinin treatment, hyper-reactive malarial splenomegaly (HMS), and splenic rupture)[4]
• Blackwater fever and hemoglobinuria due to intravascular hemolysis in patients with severe clinical manifestations of falciparum malaria[13]
• Profound thrombocytopenia is often associated with P. falciparum infection, however, bleeding and disseminated intravascular coagulation (DIC) are rare.[13]
• Hepatic dysfunction[13]
• Shock and associated infections (such as Salmonella bacteriemia, aspiration pneumonia, nosocomial infections, etc.)[3][13]
• Neurological sequelae (epilepsy, permanent focal deficits, etc.)[4]

The three most common complications occurring in children are cerebral malaria, severe anemia, and acidosis, either isolated or overlapping.[20]

Although no intervention for preventing the infection is 100% effective, there are several different approaches available that can be used alone or in combination. Personal protective measures reduce the risk of exposure to infective mosquitoes, and chemoprophylaxis can aid in reducing the risk of a poor outcome if infected.[26] A common approach usually applied is an “ABCD” of malaria – A standing for awareness of the risk, B for bite avoidance, C for compliance with chemoprophylaxis, and D for diagnosis in case of fever. It is essential to consider traveler´s health (especially pregnancy, age, immunosuppression) when assessing the risk for developing severe malaria and choosing an appropriate antimalarial drug.[10]

It is necessary to emphasize the importance of personal protective measures such as barrier clothing, insecticide-impregnated bed nets, application of effective mosquito repellent (higher percentage of active ingredient provides longer protection), and spraying the residence with insecticide. Products that contain 20%-40% of DEET (N, N-Diethyl-meta-toluamide), picaridin, oil of lemon eucalyptus or PMD (p-menthane-3,8-diol) and IR3535 are recommended. Behaviors to minimize exposure to mosquitos are also encouraged – for instance, staying indoors from dusk till dawn, choosing screened accommodations.[9][26] Indoor residual spraying and long-lasting insecticidal nets remain to be the most effective tools for malaria control and elimination, despite the emergence of insecticide-resistant Anopheles mosquitos.[27][28]

A standard recommendation for all travelers to endemic areas is strict compliance with the antimalarial drug. There are several different drug choices, prescribed after assessing individual´s risk (level of local transmission, duration of exposure, rural vs. urban travel, type of travel and season), travelers health status, present contraindications, level of parasite drug resistance (mostly chloroquine and mefloquine resistance) and traveler’s preference based on schedule, cost and nature of possible side effects. There is an increasing problem with counterfeit and substandard medications being sold in several Sub-Saharan countries, and travelers should be advised to buy the needed medications before departure.[29][10] A complete list of recommendations for drug choice can be found on the CDCs website – Malaria Information by Country.

As pregnant women are at increased risk for severe malaria, the WHO and other organizations recommend not traveling to the endemic areas.[10]

Travelers to the endemic areas, former residents of malaria-endemic areas and people diagnosed with malaria should be informed, as per Food and Drug Administration (FDA) recommendations, that they may not donate blood for 1 year after travel or 3 years after departing or revisiting the country or for 3 years after treatment, respectively.[9]

Travelers should be informed that malaria can be fatal with delayed treatment, and one should, therefore, seek medical attention while abroad if symptoms of malaria develop and not fly back for treatment, as medical treatment may not be readily available on transit.[9]

Malaria vaccine would be an ideal tool to control, prevent, eliminate, and ultimately eradicate the disease. The complexity of P. falciparum infection has hindered several attempts at developing an effective vaccine, yet the acquisition of partial immunity and successful treatment of malaria with purified immunoglobulins from semi-immune adults showed that the development of a vaccine is attainable. Researchers have identified several potential targets in the parasite´s infectious cycle. Currently, 20 vaccine candidates are undergoing clinical trials.[27] The most promising and most advanced vaccine to be developed so far is a licensed RTS, S subunit vaccine (RTS, S/ASO1), targeting the pre-erythrocytic stage of infection, thus preventing hepatocyte infection and parasite development, consequently limiting RBC invasion. It consists of a recombinant protein of the P. falciparum circumsporozoite protein (CSP) conjugated to the hepatitis B surface antigen.[27] RTS, S/ASO1, the first malaria vaccine which has received regulatory approval for human use, was used to start the first routine malaria vaccination program in Africa – a pilot study in Malawi in April 2019, which has since expanded to Kenya and Ghana. The pilot study is planned to last about 50 months and to enroll 720 000 children in vaccination and control clusters, however several safety concerns, that are now being investigated in the pilot study, have already been identified in phase III trials:  higher risk of meningitis, cerebral malaria and doubled female mortality. If no serious safety concern is determined in the first 24 months of trial, the pilot study will run its full course before any decision will be made about its broader use in endemic countries.[30]

There has been an emergence of a (widely used) pyrethroid insecticide-resistant malaria vector population, causing extensive research with their first results suggesting a better effect of long-lasting insecticidal nets treated with PBO (piperonyl butoxide) instead of pyrethroid laced nets.[28]

Most cases of malaria in the U.S. are imported and could, therefore, be avoided with appropriate personal protective measures and compliance with prescribed chemoprophylaxis. Health care providers on all levels must be educated not only on the diagnosis and treatment of malaria but especially on the importance of prevention. They should be able to provide enough information to travelers at risk. Travelers to the endemic areas should obtain appropriate clothing, insecticides, and other protective gear based on the information offered by health care providers and CDC. Collaboratively, a physician and a pharmacist, should decide on, recommend and prescribe appropriate chemoprophylaxis, considering traveler's personal preferences, time of travel, current health status, risk factors, drug-drug interactions, and possible contraindications, while emphasizing the importance of compliance with the drug-taking regimen. 

The crucial issue in the diagnosis and treatment of malaria is the consideration of the possibility of diagnosis. Expert advice from an infectious disease or travel medicine specialist should be sought once malaria is a suspected diagnosis, especially in the setting of severe disease.[24] The execution of a microscopic analysis of a stained blood smear often depends on several factors such as laboratory equipment, quality of reagents, and laboratorian expertise. Laboratorians should, therefore, be trained in the preparation and analysis of blood-smears to diagnose a malarial infection correctly. The results need to be communicated back to the physician as soon as possible. All laboratory-confirmed cases of malaria should be reported to CDC to help with their surveillance efforts. Healthcare providers that are a part of the interprofessional team (nurses, respiratory therapists, physicians, etc.) managing patients with severe malaria in critical or intensive care units, should be educated on early recognition of complications.