Author: Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, , Dayton and Montgomery County (Ohio) Clinic

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious Diseases Society of America, Infectious Diseases Society of Ohio.

Co-author: Ryan Q Simon, MD Infectious Disease Specialist, Wright State Physicians, Wright State University of Medicine

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Centre; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Additional Contributors

Emilio V Perez-Jorge, MD, FACP Staff Physician, Division of Infectious Diseases, Lexington Medical Centre

Emilio V Perez-Jorge, MD, FACP is a member of the following medical societies: American College

1 of Physicians-American Society of Internal Medicine, Infectious Diseases Society of America, Society for Healthcare of America, South Carolina Infectious Diseases Society

Acknowledgements

Michael Stuart Bronze, MD Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Centre

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation

Joseph Richard Masci, MD Professor of Medicine, Professor of Preventive Medicine, Mount Sinai School of Medicine; Director of Medicine, Elmhurst Hospital Centre

Joseph Richard Masci, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, Association of Professors of Medicine, and Royal Society of Medicine

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Centre College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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Course Content Malaria Practice Essentials Signs and Symptoms History Diagnosis Approach Considerations Imaging Studies Microhematocrit centrifugation Fluorescent dyes/ultraviolet indicator tests Polymerase chain reaction assay Lumber puncture Blood smears Thick smears Thin smears Alternative to Blood Smear testing Rapid diagnostic tests (RDT) Other tests Management Approach Considerations Pregnancy Pediatrics Diet and Activity Monitoring Pharmacologic Therapy Pharmacologic treatment in pregnancy Inpatient Care Deterrence and prevention Investigational malaria vaccines Consultation Summary

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Malaria Practice Essentials

Malaria is a potentially life-threatening disease caused by infection with transmitted by an infective female .

Plasmodium falciparum infection carries a poor prognosis with a high mortality if untreated, but it has an excellent prognosis if diagnosed early and treated appropriately. See the image below.

Malarial merozoites in the peripheral blood. Note that several of the merozoites have penetrated the erythrocyte membrane and entered the cell.

Signs and symptoms

Patients with malaria typically become symptomatic a few weeks after infection, though the symptomatology and incubation period may vary, depending on host factors and the causative species. Clinical symptoms include the following:

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• Headache (noted in virtually all patients with malaria)

• Cough

• Fatigue

• Malaise

• Shaking chills

• Arthralgia

• Myalgia

• Paroxysm of fever, shaking chills, and sweats (every 48 or 72 hours, depending on species)

Less common symptoms include the following:

• Anorexia and lethargy

• Nausea and vomiting

• Diarrhea

• Jaundice

Most patients with malaria have no specific physical findings, but splenomegaly may be present. Severe malaria manifests as the following:

• Cerebral malaria (sometimes with coma)

• Severe anemia

• Respiratory abnormalities: Include metabolic acidosis, associated respiratory distress, and pulmonary edema; signs of malarial hyperpneic syndrome include alar flaring, chest retraction, use of accessory muscles for respiration, and abnormally deep breathing

• Renal failure (typically reversible)

History

In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they travelled 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 he or she may have; and that he or she may be using.

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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 also include the following:

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

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 fevers spikes a day. Indeed, the periodicity of fever associated with each species (i.e. 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 is often 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 .

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. In addition, 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 , 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 has sometimes been misdiagnosed.

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Plasmodium falciparum is the most common of the four human malaria parasites across much of Sub- Saharan Africa.

Because P malariae infection is typically relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographical 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.

Diagnosis The patient history should include inquiries into the following:

• Recent or remote travel to an endemic area

• Immune status, age, and pregnancy status

• Allergies or other medical conditions

• Medications currently being taken

The following blood studies should be ordered:

• Blood culture

• Hemoglobin concentration

• Platelet count

• Liver function

• Renal function

• Electrolyte concentrations (especially sodium)

• Monitoring of parameters suggestive of hemolysis (haptoglobin, lactic dehydrogenase [LDH], reticulocyte count)

• In select cases, rapid HIV testing

• White blood cell count: Fewer than 5% of malaria patients have leukocytosis; thus, if leukocytosis is present, the differential diagnosis should be broadened

• If the patient is to be treated with primaquine, glucose-6-phosphate dehydrogenase (G6PD) level

• If the patient has cerebral malaria, glucose level to rule out hypoglycemia

The following imaging studies may be considered:

• Chest radiography, if respiratory symptoms are present

• Computed tomography of the head, if central nervous system symptoms are present

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Specific tests for malaria infection should be carried out, as follows:

• Microhematocrit centrifugation (sensitive but incapable of speciation)

• Fluorescent dyes/ultraviolet indicator tests (may not yield speciation information)

• Thin (qualitative) or thick (quantitative) blood smears (standard): Note that 1 negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36- hour period

• Alternatives to blood smear testing (used if blood smear expertise is insufficient): Include rapid diagnostic tests, polymerase chain reaction assay, nucleic acid sequence-based amplification, and quantitative buffy coat

Histologically, the various Plasmodium species causing malaria may be distinguished by the following:

• Presence of early forms in peripheral blood

• Multiply infected red blood cells

• Age of infected RBCs

• Schüffner dots

• Other morphologic features

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Approach Considerations

In returning travellers from endemic areas, malaria is suggested by the triad of thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, and atypical lymphocytes. These findings should prompt them to obtain malarial smears.

In general, blood cultures should be drawn in a febrile patient. Patients from tropical areas may have more than 1 infection; maintaining a high suspicion for additional infections should be considered when patients do not respond to antimalarials.

Assess hemoglobin (decreased in 25% of patients, often profoundly in young children), platelet counts (thrombocytopenia in 50-68% of patients), and liver function (results abnormal in 50% of patients). Also monitor renal function, electrolytes (especially sodium), and parameters suggestive of hemolysis (haptoglobin, LDH, reticulocyte count). Rapid HIV testing may also be indicated in select cases. Importantly, fewer than 5% of patients with malaria have an elevated white blood cell (WBC) count. If leukocytosis is present, the examiner should entertain a broader list of differential diagnoses. The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria.

If the patient is to be treated with primaquine, a G-6-PD level should be obtained because primaquine can result in severe hemolysis in these patients.

If the patient has cerebral malaria, obtain a blood glucose level to rule out hypoglycemia as a cause of mental-status changes. Note that intravenous (IV) quinine can induce hypoglycemia; therefore, blood glucose should be monitored when IV quinine is used.

The British Committee for Standards in Haematology revised its Guidelines for the Laboratory Diagnosis of Malaria, intended for use in the United Kingdom but also potentially applicable to other nonendemic areas. Recommendations include the following:

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• Thick and thin films should be routinely used for malaria diagnosis; thick films should be stained with Giemsa or Field stain, thin films with Giemsa or Leishman stain

• Two observers should examine thick films, with each viewing a minimum of 200 high-power fields; if the films are positive, the species should be determined through examination of a thin film

• In cases of P falciparum or Plasmodium knowlesi infection, the percentage of parasitized cells or the number of parasites per microliter should be estimated

• Rapid diagnostic tests for malarial can be used on a supplementary basis when diagnosis is performed by inexperienced staff

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

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

Fluorescent dyes/ultraviolet indicator tests

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

Polymerase chain reaction assay

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

Lumbar puncture

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

Blood Smears

A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear. In rare occasions, P falciparum infection can present without detectable parasitemia. If no alternative diagnosis is found in an at-risk patient with possible cerebral malaria (ie, unrevealing lumbar puncture findings), initiate therapy for presumptive malaria and continue to obtain additional blood smears to confirm the diagnosis.

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When reading a smear, 200-300 oil-immersion fields should be examined (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. Thick smears Three thick and thin smears 12-24 hours apart should be obtained. 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 20 times more sensitive than thin smears, but speciation may be more difficult. The parasitemia can be calculated based on the number of infected RBCs. This is a quantitative test. Thin smears Thin smears are less sensitive than thick smears, but they allow identification of the different species. This should be considered a qualitative test.

Alternatives to Blood Smear Testing

Alternative diagnostic methods typically are used if the laboratory does not have sufficient expertise in detecting parasites in blood smears. Rapid diagnostic tests (RDT) Immunochromatographic tests based on to histidine-rich protein-2 (PfHRP2), parasite LDH (pLDH), or Plasmodium aldolase appear to be very sensitive and specific. Some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification. Only one RDT (BinaxNOW) has been approved to date for the diagnosis of malaria in the United States.

In one study, RDTs were found to perform 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. A recent 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.

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.

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

The quantitative buffy coat (QBC) is a technique that is as sensitive as thick smears. Because results cannot be used to speciate Plasmodium, a thin smear must be examined.

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Malaria is a reportable disease. Identification of parasites by any of the above techniques should prompt notification to the authorities.

Management Treatment is influenced by the species causing the infection, including the following:

• Plasmodium falciparum

• P vivax

• P ovale

• P malariae

• P knowlesi

In the United States, patients with P falciparum infection are often treated on an inpatient basis to allow observation for complications. Patients with non– P falciparum malaria who are well can usually be treated on an outpatient basis.

General recommendations for pharmacologic treatment of malaria are as follows:

• P falciparum malaria: Quinine-based therapy is with quinine (or quinidine) sulphate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine; alternative therapies are artemether-lumefantrine, atovaquone-, or

• P falciparum malaria with known susceptibility (only a few areas in Central America and the Middle East): Chloroquine

• P vivax, P ovale malaria: Chloroquine plus primaquine

• P malariae malaria: Chloroquine

• P knowlesi malaria: Same recommendations as for P falciparum malaria

Pregnant women (especially primigravidas) are up to 10 times more likely to contract malaria than nongravid women and have a greater tendency to develop severe malaria. Medications that can be used for the treatment of malaria in pregnancy include the following:

• Chloroquine

• Quinine

• Atovaquone-proguanil

• Clindamycin

• Mefloquine

• Sulfadoxine-pyrimethamine (avoid in first trimester)

• Artemether-lumefantrine

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Approach Considerations

Failure to consider malaria in the differential diagnosis of a febrile illness in a patient who has travelled to an area where malaria is endemic can result in significant morbidity or mortality, especially in children and in pregnant or immunocompromised patients.

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 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 infection are often treated on an inpatient basis in order to observe for complications attributable to either the illness or its treatment. Pregnancy Pregnant women, especially primigravid women, are up to 10 times more likely to contract malaria than nongravid women. Gravid women who contract malaria also have a greater tendency to develop severe malaria. Unlike malarial infection in nongravid individuals, pregnant women 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 women in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis.

If a pregnant woman becomes infected, she 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 foetus. 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 women are limited to mefloquine or quinine plus clindamycin. Although the limited availability of quinine and increasing resistance to mefloquine limit these options, strong evidence now 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 now recommends the use of artemether-lumefantrine as an additional treatment option for uncomplicated malaria in pregnant women in the United States during the second and third trimester of pregnancy at the same doses recommended for nonpregnant women.

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

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

Most antimalarial drugs are very effective and safe in children, provided that the proper dosage is administered. Children commonly recover from malaria, even severe malaria, much faster than adults. Diet and activity Patients with malaria should continue intake and activity as tolerated. Monitoring Patients with non– P falciparum malaria who are well can usually 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.

Pharmacologic Therapy

IV preparations of antimalarials are available for the treatment of severe complicated malaria, including artesunate and quinidine gluconate, which is used as a substitute for the IV quinine available in countries outside of the United States.

In a 2010 randomized study done in 11 African centres, 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.

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

P falciparum drug resistance is common in endemic areas, such as Africa. Standard antimalarials, such as chloroquine and antifolates (sulfadoxine-pyrimethamine), 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 now 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 ’s, a new class of antimalarial agent.

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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. Rectal artesunate has been used for pre-treatment of children in resource-limited settings as a bridge therapy until the patient can access health care facilities for definitive IV or oral therapy.

Despite their being a fairly new antimalarial class, resistance to artemisinin’s has been reported in some parts of southeast Asia (Cambodia).

In the United States, artemether and lumefantrine tablets (Coartem) can be used to treat acute uncomplicated malaria. Artesunate, a form of artemisinin that can be used intravenously, is available from the Centres for Disease Control and Prevention (CDC). Other combinations, such as atovaquone and proguanil HCL (Malarone) or quinine in combination with doxycycline or clindamycin, remain highly efficacious.

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. It has also 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.

The following is a summary of general recommendations for the treatment of malaria:

• P falciparum malaria - Quinine-based therapy is with quinine (or quinidine) sulfate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine; alternative therapies are artemether-lumefantrine, atovaquone-proguanil, or mefloquine • P falciparum malaria with known chloroquine susceptibility (only a few areas in Central America and the Middle East) - Chloroquine • P vivax, P ovale malaria - Chloroquine plus primaquine; however, a 2012 study of Indonesian soldiers demonstrated that primaquine combined with newer nonchloroquine antimalarials killed dormant P vivax parasites and prevented malaria relapse; the combination of dihydroartemisinin-piperaquine with primaquine had 98% efficacy against relapse, suggesting that this regimen could become a useful alternative to primaquine plus chloroquine, the clinical utility of which is being threatened by worsening chloroquine resistance • P malariae malaria – Chloroquine • P knowlesi malaria – Recommendations same as those for P falciparum malaria.

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 (e.g. chloroquine) for acute P vivax malaria. Approval was based on an international program of more than 4000 participants.

In one of the clinical trials, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 89.2% with tafenoquine 300 mg and 91.9% with tafenoquine 600 mg compared with chloroquine alone (37.5%). The results showed a significantly improved treatment difference compared with chloroquine alone of 51.7% (P< 0.0001) with tafenoquine 300 mg and 54.5% (P< 0.0001) with tafenoquine 600 mg.

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Because tafenoquine increases the risk of 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.

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.

In July 2013, the FDA updated its warning about mefloquine hydrochloride to include neurologic side effects, along with the already known risk of 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.

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 (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.

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.

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 of miscarriage.

Use of tafenoquine to prevent relapse of P vivax malaria during pregnancy is not recommended. Use during pregnancy may cause hemolytic anemia in a G6PD-deficient foetus. In addition, tafenoquine use during lactation should be avoided if the infant is G6PD deficient or of unknown G6PD status.

Inpatient Care

Patients with elevated parasitemia (>5% of RBCs infected), CNS infection, or otherwise severe symptoms and those with P falciparum infection should be considered for inpatient treatment to ensure that medicines are tolerated.

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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 (e.g. chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health or cause any symptoms.

Deterrence and Prevention

Avoid mosquitoes by limiting exposure during times of typical blood meals (i.e. dawn, dusk). Wearing long-sleeved clothing and using insect repellents may also 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 is no longer exposed to potential mosquito bite. Consider using bed nets that are treated with permethrin. While this is an effective method for prevention of malaria transmission in endemic areas, an increasing incidence of pyretrhoid resistance in Anopheles spp has been reported. 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 traveller and any medical conditions the traveller may have that contraindicate the use of a specific drug.

Before traveling, people should consult their physician and the Malaria and Traveller’s Web site of the CDC to determine the most appropriate chemoprophylaxis. Travel Medicine clinics are also a useful source of information and advice. Investigational Malaria vaccine production and distribution continues to be in the research and development stage. In 2015, European Union (EU) regulators approved the world's first malaria vaccine for use outside the EU among children aged 6 weeks to 17 months. The new vaccine (Mosquirix, GlaxoSmithKline Biologicals), as of April 2019, is entering a large-scale pilot test in Malawi, followed by Kenya and Ghana. The vaccine is to be administered to 360,000 children aged 2 years or younger to evaluate efficacy and feasibility. In trials, the vaccine reduced malaria episodes by 40%. Mosquirix targets P falciparum. It limits the parasite's ability to infect, mature, and multiply in the liver.

Interim phase 3 trial results were reported in 2011 for the malaria vaccine RTS,S/AS01. The results included 6000 African children aged 5-17 months who received the malaria vaccine or a comparator vaccine and were followed for 12 months. The incidence of malaria was 0.44 case per person-year in the RTS,S/AS01 group, compared with 0.83 case per person-year in the comparator vaccine group. The vaccine efficacy rate was calculated to be 55.8%.

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Consultations

Consider consulting an infectious disease specialist for assistance with malaria diagnosis, treatment, and disease management. The CDC is an excellent resource if no local resources are available.

Pregnant patients with malaria are at increased risk of morbidity and mortality. In addition, nonimmune mothers and immune primigravidas may be at an increased risk of low birth weight, foetal loss, and prematurity. Consult an expert in malaria to determine the safest and most effective prophylaxis or treatment in a pregnant woman.

Medication Summary

The 4 major drug classes currently 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 of 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 he or she is 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. A patient presenting with cyanosis and a normal PaO2 on room air should be suspected of having methemoglobinemia.

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