MALARIA

MALARIA

Current diagnosis

History

• Does the patient have a fever? Any other flulike symptoms (chills, sweats, headache, muscle aches, nausea, and/or vomiting)?

• Did the patient travel to a malaria-endemic area? And, how long did the travel precede symptom onset?

• What Plasmodia species are known to be present in the area(s) of travel and what corresponding drug-resistance patterns are present?

• Did the patient use appropriate prophylaxis for the region and adequate personal protective measures during travel?

Diagnosis

•   Thick and thin blood smears are required for detection, Plasmodium speciation, and parasite density determination.

• Use of rapid diagnostic tests for quick detection must be followed by blood smears to confirm diagnosis and monitor parasite density.

• Be mindful of severe disease signs including acidosis, acute respiratory distress, altered consciousness, high parasite density (> 5%), hyperbilirubinemia, hypotension, renal impairment, seizures, and severe anemia.

Current therapy

• Develop treatment plan based on prompt laboratory confirmation of Plasmodium species and drug-resistance patterns of Plasmodium species in known area(s) of travel.

• If severe disease is a concern, parenteral artesunate10 should be used, where available, or quinidine, and the patient should be monitored in an intensive care setting providing supportive care as needed.

• For uncomplicated disease, consider hospital admission for likely P. falciparum infection.

•   Administer oral therapies (i.e., artemisinin-based combination therapies or chloroquine) based on resistance patterns in area of travel.

•   To prevent relapse, prescribe primaquine to all with a normal glucose-6-phosphate dehydrogenase (G6PD) status and travel to areas having known P. vivax and P. ovale.1

10 Available in the United States from the Centers for Disease Control and Prevention.

1 Not FDA approved for this  indication.

Malaria is a potentially fatal parasitic disease caused by intraerythrocytic protozoa of the genus Plasmodium and is transmitted to humans primarily via female Anopheles mosquito bites. Often considered by many the most important parasitic disease affecting human beings, in 2015 it accounted for over 200 million infections and an estimated 438,000 deaths worldwide, mainly in young children, and it remains a focus of international concern. Thankfully, in the past 15 years, due in part to substantial increases in donor funding (i.e., The Global Fund, World Bank, UNICEF, and United States Agency for International Development) advances in treatment and control measures, and increased enthusiasm for elimination, there has been a significant drop in the infection and mortality rates associated with this disease by 18% and 48%, respectively. Interestingly we have witnessed a very gradual increase in the number of malaria cases in the United States largely due to more tourism to malaria-endemic locations, especially Africa. In 2012, a total of 1687 malaria cases were reported in the United States, which, though somewhat lower than the year prior when reported malaria cases were at a 40-year high, represents an overall upward trend.

By far, the majority of patients developing malaria in the United States are infected during travel to other countries. Whether or not preventive measures were appropriately used, health-care workers should have a high index of suspicion for malaria in the returning traveler with fever and other flulike symptoms. Since cases are rare in North America, misdiagnosis is not uncommon. Clinicians, therefore, must consider malaria in the differential for any febrile illness in an individual who has traveled to an area of known malaria transmission in the past several months or in those with fever of unknown origin regardless of travel history. Since untreated malaria infections can lead to anemia, pulmonary edema, renal failure, coma, and even death, prompt diagnosis and treatment are essential.

Epidemiology

According to the 2015 World Health Organization (WHO) World Malaria Report, 3.2 billion people were considered at risk for malaria and 97 countries reported active transmission (see Figure 1). Though 80% of cases and fatalities are accounted for in 15 sub-Saharan African countries, Asia and Central and South America also have significant disease burden with Europe and the Middle East accounting for a smaller portion of cases. P. falciparum is the most prevalent form of malaria in Africa and is responsible for more deaths worldwide than other Plasmodia species, and 70% of fatalities are in patients under 5 years of age. Though P. falciparum is encountered outside Africa, P. vivax is often more prevalent across much of Asia and Central and South America and transmission rates are more frequently low and seasonal. Meanwhile, rates of transmission are much higher across sub-Saharan Africa and parts of Oceania, where P. falciparum predominates. P. vivax is responsible for most relapsing malarial disease, though P. ovale is also responsible but to a lesser extent.

FIGURE 1    Malaria-endemic countries in the (A) Western and  (B) Eastern Hemispheres. Transmission occurs across most of Africa, Central and South America, and Southern and Southeast Asia, as well as parts of the Caribbean, Eastern Europe, and the South  Pacific.

Countries are shaded completely even if the area of endemicity is only in a small area of the country. (Adapted from Centers for Disease Control and Prevention. CDC Health Information for International Travel 2016. New York: Oxford University Press; 2016. Public Domain.)

In endemic areas of high, stable transmission, partial immunity can develop after many years of repeat exposure to infectious mosquito bites, and young children often show resistance to severe forms of the disease by the age of 5. By adolescence they also often become resistant to more uncomplicated forms of the disease. Though resistant to clinical malaria, rarely will one become completely resistant to actual infection. In areas of unstable or seasonal transmission (i.e., sub-Sahel region of Africa), transmission can be intense but is isolated to rainy periods and full protective immunity does not develop so symptomatic disease may occur across all ages.

There are also varying drug-resistance patterns that greatly affect prevention, treatment, and mortality. Resistance to antimalarial medications continues to be an important consideration when considering treatment, especially P. falciparum infection. By the 1970s, Pfalciparum chloroquine resistance had been confirmed on every continent where malaria was endemic, and currently only the

Caribbean, areas of Central America west of the Panama Canal, and a few Middle Eastern countries show sensitive strains. P. vivax has also shown resistance to chloroquine in areas of Indonesia and Papua New Guinea. Mefloquine, too, is currently no longer recommended to treat P. falciparum infections originating from Southeast Asia due to increasing levels of resistance, and even artesunate and its partner drugs are showing signs of decreased effectiveness across the Mekong Region in Southeast Asia. When in doubt, clinicians should use the Centers for Disease Control and Prevention’s (CDC) online interactive malaria map (http://www.cdc.gov/malaria/map/) or Malaria-by- Country tables (http://www.cdc.gov/malaria/travelers/country_table/a.html) to quickly view the types of Plasmodium present and resistance characteristics found in the patient’s area of travel.

Risk Factors for Transmission

Risk factors for malaria include both individual risk and environmental conditions that increase transmission rates. Anyone traveling to or living in a malaria-endemic area is at risk for transmission. Children, elderly, pregnant women, and HIV/AIDS patients are at higher risk than the general population. HIV-related immunosuppression, especially, may lead to more severe manifestations of malaria. Because of lack of partial immunity, travelers to endemic regions also have a higher risk of transmission. Also, given the known reductions that can occur via the use of personal protective measures (i.e., insecticide-treated bed nets and insect repellents) and chemoprophylaxis, individuals without access to or noncompliant with these measures are at increased risk. Malaria can also be transferred from mother to baby across the placenta (congenital malaria) or during birth. Though rare, there are some cases of malaria transmission during blood transfusion as well as organ transplantation.

At the population level, there are many conditions that increase transmission as well, most of which relate to effects on any of the 30 or so Anopheles species linked to malaria transmission. The rainy season allows for eggs of Anopheles mosquitoes to be laid in water more readily and larvae to develop more easily. Transmission is also higher in regions with longer mosquito lifespans and in areas where humans are the choice blood meal over other animals. In addition, elevation, temperature, and humidity of a region all contribute to transmission efficiency of malaria.

Etiology and the Parasite’s Life Cycle

There are five species of Plasmodium indicated in human malarial disease: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. P. knowlesi classically was identified as a simian disease; however, it has become an appreciable cause of malaria in humans in Southeast Asia. The life cycle (Figure 2) of the malaria parasite differs slightly among Plasmodium species and these differences explain how species present differently. For instance, the time from initial infection to symptom presentation varies across species. P. knowlesi incubation is from 9 to 12 days and P. falciparum is often 9 to 14 days, while P. vivax ranges from 12 to 17 days and P. ovalefrom 16 to 18 days. P. malariae is the most variable with ranges from 18 to 40 or more days.

FIGURE 2    The malaria parasite life cycle involves two hosts. During  a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver cells (2) and mature into schizonts (3), which rupture and release merozoites (4). (In Plasmodium vivax and Plasmodium ovale, a dormant stage [hypnozoites] can persist in the liver and cause relapses by  invading the bloodstream weeks to years later.) After initial replication in the liver via exoerythrocytic cycle or tissue schizogony (A), the parasites undergo asexual multiplication in erythrocytes via erythrocytic cycle or blood schizogony (B). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture, releasing merozoites (6). Some parasites differentiate into sexual erythrocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal (8). The parasites’ multiplication in the mosquito is known as the sporogonic cycle  (C).

While in the mosquito’s stomach, the microgametes penetrate the macrogametes, generating zygotes (9). The zygotes in turn  become motile and elongated (ookinetes) (10) and invade the midgut wall of the mosquito, where they develop into oocysts (11). The oocysts grow, rupture, and release sporozoites (12), which make their way to the mosquito’s salivary glands. Inoculation of the sporozoites (1) into a new human host perpetuates the malaria life  cycle.

Regardless of species, the life cycle starts when an infected female Anopheles mosquito takes a human blood meal, injecting anywhere from 10 to 100 Plasmodium sporozoites into the host. The sporozoites travel to the liver, invading hepatic cells where they then replicate and each divides forming 10,000 to more than 30,000 merozoites (haploid cells). The species determines how quickly this happens and how many merozoites are formed. In the liver, P. vivax and P. ovale produce another form, called hypnozoites, which remain in the liver for an extended time and are responsible for relapsing illness, sometimes months to even years after initial infection. The merozoites enter circulation and invade red blood cells (RBCs) (asexual replication).

Once inside RBCs, the merozoites develop into schizonts, rupture, and more merozoites are released into the bloodstream to invade RBCs.

Depending on the species, this cycle can repeat anywhere from 24 to 72 hours. Typically, the number of merozoites in the bloodstream is proportional to disease severity for a given species. However, this is not always the case as sometimes severe disease is seen even in small numbers of infected RBCs, especially in the case of P. falciparum. Some merozoites develop into male and female gametocytes entering a sexual stage. Gametocytes enter into the bloodstream where an Anopheles mosquito partakes of a blood meal, ingesting the gametocytes, and then these gametocytes develop into gametes in the mosquito midgut. Male and female gametocytes sexually reproduce to form oocysts, which then grow and release sporozoites. The sporozoites travel to the salivary gland and with a subsequent human bite, complete the transmission cycle.

It is worth noting that all Plasmodium species may cause recrudescence, which happens when treatment is suboptimal and parasite clearance incomplete. In these cases, patients may show symptoms of infection months to years after initial infection. Patient immunosuppression also furthers this risk. In endemic areas, recurrent P. falciparum and P. vivax malaria can have pronounced negative effects in children affecting growth, development and schooling.

Clinical Manifestations

The most common presentation of malaria is fever after travel to an endemic area. Fever and chills are the chief complaint in 96% of patients, followed by headaches and muscle aches in 79% and 60%, respectively. The classic “paroxysm” of symptoms includes chills for minutes to hours, followed by high fevers when RBCs rupture and merozoites are released, and then sweating and fever breaking.

However, the paroxysm is often not present. Also, P. falciparum tends to cause a continual fever with spikes as opposed to the cyclical nature of the other species; therefore, absence of paroxysm should not be used to rule out malaria. General malaise, weakness, fatigue, and muscle aches are common. Less common, are palpable liver and/or spleen, nausea and vomiting, abdominal pain, and diarrhea. More severe cases can present with jaundice, confusion, orthostatic hypotension, or seizures depending on the type of malaria and severity.

Most patients will develop anemia and splenomegaly as the spleen acts to remove both infected and noninfected RBCs from the bloodstream. Thrombocytopenia will occur in most patients as well, along with elevations in aspartate aminotransferase and alanine transaminase. Acute kidney injury is common, especially in more severe malaria. P. falciparum and P. knowlesi typically cause higher parasitemia than P. vivax, P. ovale, and P. malariae because the former two are less selective in their invasion of RBCs. Infection can quickly lead to severe disease and death if not treated promptly, and so rapid, correct diagnosis can greatly improve survival probability.

P. falciparum causes more severe disease and death than the other species. The parasite causes RBCs to develop “knobs,” which express PfEMP1, proteins regulating adhesion to endothelium of capillaries and postcapillary venules. The RBCs are also more rigid. The combination of adhesion to endothelium and rigid RBCs obstructs the vessels, also known as sequestration. Sequestration is implicated in severe disease and leads to metabolism of glucose locally, local tissue factor recruitment, edema, and ultimately end organ damage.

Sequestration in brain tissues is better described, but it is thought to occur in lung tissue as well. Sequestration is thought to increase intracranial blood pressure. Interestingly cerebral edema is frequently seen in children, but not in adults radiographically. Cerebral edema, seizures, coma, and death can be immediate sequelae of P. falciparum. While adult survivors typically do not have lasting neurologic effects, 3% to 15% of children survivors have lasting neurological deficits from P. falciparum infection. Cerebral palsy, learning disability, language deficits, and epilepsy are some of the lasting effects in children survivors of P. falciparum.

Cerebral malaria, severe anemia, pulmonary edema, and renal failure are examples of end organ failure that can result and quickly lead to severe morbidity and death if not treated correctly and rapidly. Although P. falciparum is the prominent cause of severe malaria and death, other species of Plasmodium can also develop complications and lead to death if not adequately diagnosed and treated.

Outside of Africa, P. vivax accounts for roughly half of all malaria cases and, though often having a much lower case-fatality rate than P. falciparum, it still may cause a debilitating febrile illness with progressive anemia and, sometimes causes severe disease including symptoms of thrombocytopenia and acute pulmonary edema. Less common symptoms can include cerebral malaria, pancytopenia, jaundice, splenic rupture, acute renal failure, and shock. Prompt management of these severe cases and treatment in a manner similar to P. falciparum infection are recommended.

Chronic malaria infection, characterized by low-level parasitemia, may lead to a variety of complications. For instance, recurrent P. vivax infections or relapses may lead to hyperactive malarial splenomegaly that leads to significant anemia, hypersplenism, and hypergammaglobulinemia. Meanwhile, persistent P. malariae infection has been linked to risk for nephrotic syndrome in parts of Africa.

Diagnosis

Correctly diagnosing malaria and identifying Plasmodium species quickly is paramount to appropriate timely treatment, and testing should be done whether or not an appropriate chemoprophylaxis regimen was followed. Unfortunately, malaria may mimic many diseases due to its common symptom profile, especially high fevers. Other causes of fever including more common bacterial and viral illnesses (i.e., bacterial meningitis, influenza, and acute hepatitis) and tropical diseases such as dengue fever, chikungunya, rickettsial infections, typhoid, and trypanosomiasis, must be considered.

Together, thick and thin smear microscopy are still considered the gold standard for malaria diagnosis, and they are best performed by experienced personnel without delay on any patient presenting with fever and travel to endemic areas. These tests help to answer three questions: Is there malaria present? What species is present? And, what percentage of RBCs are infected?

The general process of microcopy is described here, but strict protocols should be followed to give reliable and reproducible results. Blood is sampled through finger stick or venipuncture, and the thick smear is air dried and not fixed; therefore, hemolysis occurs. Thick smears are more sensitive at identifying infection, as they concentrate parasites, and may also help estimate parasite concentration.

However, hemolysis during preparation makes it difficult to identify species-level characteristics using thick smear microscopy. The thin smear is fixed with air drying and methanol and, since RBCs remain intact, can reveal the species of Plasmodium present and the percentage of RBCs infected, which serves as a marker for parasitemia and eventually treatment effectiveness. Both slides are stained, typically with Giemsa (pH of 7.2) and slides should be examined under 1000 × oil immersion for at least 20 minutes and 200 high-powered fields before reporting as negative. Negative smears should be repeated every 8 to 12 hours until malaria can be ruled out confidently as symptoms may precede parasitemia. The CDC recommends confirming the diagnosis before treating for malaria; however, with symptoms of suspected severe malaria, it may be appropriate to treat before diagnosis to start treatment rapidly. For further information including slide preparation and diagnostic assistance, clinicians may refer to the CDC’s Laboratory Identification of Parasitic Diseases website: http://www.cdc.gov/dpdx/malaria/dx.html.

In addition to direct microscopy, other diagnostic tests are available, such as rapid diagnostic tests (RDTs), polymerase chain reaction (PCR), and serology. Where available, RDTs are immunochromatographic tests that use a dipstick or cassette format and detect specific Plasmodium antigens using a single drop of blood.

Current RDTs can target the histidine-rich protein 2 of P. falciparum (PfHRP2), a panmalarial Plasmodium aldolase (PMA), and parasite specific lactate dehydrogenase (pLDH). Often they specifically are designed to target P. falciparum, P. vivax, or nonspecific Plasmodium, and they offer a rapid way (5 to 20 minutes) to test for the presence of Plasmodium without the need for a laboratory, electricity, special equipment, or even highly experienced personnel. Though not as sensitive in instances of low parasitemia (< 100 to 200 parasites/µL), RDTs have documented sensitivities and specificities reaching up to 95% and 99%, respectively. As they do not give information on parasitemia levels and false-negative results are possible, thick and thin smears should still be performed to confirm or rule out diagnosis and determine level of parasitemia.

PCR, a molecular method based on DNA amplification, may also be used for diagnosis and offers the most accurate method of parasite detection. PCR is less prone to observer error than is microscopy and more sensitive at low levels of parasitemia. As PCR becomes more widespread, it may offer a promising alternative for diagnosis and speciation, but currently it is not widely available due to logistical constraints and the need for well-equipped laboratories and specially trained technicians. It remains an important research tool detecting drug resistance mutations and offering a secondary means of species confirmation. Likewise, a variety of serologic tests can be performed by some laboratories (i.e., CDC reference laboratories) to assess past malaria experience, but not current malaria infection.

Antimalarial Medications

A variety of malaria chemotherapy treatment and prophylaxis options are available, each with their risks, benefits, and availability issues.

Treatment options will be dictated not only by drug availability but also location of disease acquisition, infecting species, resistance patterns, and symptom severity (Table 1).

Table 1

Drug Recommendations for Treatment by Malaria Type

Diagnosis                               Drug
Uncomplicated, chloroquine-sensitive P. falciparum Chloroquine  phosphate  or hydroxychloroquine
Uncomplicated, chloroquine-resistant P. falciparum or species/resistance  unknown Artemisinin-combination therapy1 or atovaquone/proguanil or quinine sulfate7 + one of the following: doxycycline,2,3  tetracycline,2,3  clindamycin,2  or mefloquine4
Uncomplicated, chloroquine-sensitive P. malariae or P. knowlesi Chloroquine  phosphate  or hydroxychloroquine
Uncomplicated, chloroquine-sensitive P. vivax or P. ovale Chloroquine phosphate + primaquine phosphate5 or hydroxychloroquine + primaquine phosphate5
Uncomplicated, chloroquine-resistant P. vivax Atovaquone/proguanil plus primaquine phosphate5 or artemisinin-combination therapy1 + primaquine phosphate5 or quinine sulfate7 + one of the following: doxycycline,2,3 tetracycline,2,3 or clindamycin2 + primaquine phosphate5 or mefloquine4 + primaquine phosphate5
Chloroquine-sensitive malaria during pregnancy Chloroquine phosphate or hydroxychloroquine or mefloquine4
Chloroquine-resistant malaria during pregnancy Quinine sulfate7 + clindamycin2 or mefloquine4
Severe malaria Quinidine gluconate7 + one of the following: doxycycline,2,3 tetracycline,2,3 or clindamycin2 or artesunate6 followed by one of the following: artemisinin-combination therapy,1 atovaquone/proguanil, doxycycline2,3 (or clindamycin2 in pregnant women), or mefloquine4

1  Artemisinin-combination therapy; see Table 2.

2  Not FDA approved for this indication.

3  Avoid in patients under 8 years old.

4  Not recommended for infections acquired in Southeast  Asia.

5 Normal glucose-6-phosphate dehydrogenase levels should be confirmed before starting Primaquine.

6  Contact CDC for information and to obtain.

7 For infections acquired in Southeast Asia, quinine treatment should continue for 7 days. For infections acquired elsewhere, quinine treatment should continue for 3  days.

Table 2

Medications and Dosing

 

*  Available in United States through Centers for Disease Control and  Prevention.

†  Only FDA-approved artemisinin-combination  therapy.

1 Contraindicated if severe renal impairment (creatinine clearance < 30 mL/min). Not recommended for children < 5 kg and pregnant  women.

2  Contraindicated in children < 8 years of age and pregnant  women.

3 Contraindicated in people allergic to mefloquine or related compounds (quinine, quinidine) and in people with depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Not recommended for persons with cardiac conduction  abnormalities.

4 Currently category B in pregnancy (FDA), recommended as option for treatment and prophylaxis in all trimesters.

5 Contraindicated in G6PD deficiency. Also contraindicated during pregnancy and lactation, unless infant has normal G6PD level.

6 Do not give loading dose if patients have received > 40 mg/kg quinine in previous 48 hours or received mefloquine within prior 12 hours; loading dose should not be given.   Requires continuous cardiac monitoring.

7  Not FDA approved for this indication.

8  Exceeds dosage recommended by the  manufacturer.

Current antimalarial medications attack the Plasmodium organism at various stages in its life cycle. Those that kill malaria parasites when they have been released into the bloodstream during the asexual, erythrocytic cycle are referred to as blood schizonticides. Meanwhile, tissue schizonticides kill parasites during the exoerythrocytic cycle of infection in the liver and also may prevent relapse in certain species.

Some medications also have activity against gametocytes. Though not affecting the patient’s clinical response, these gametocidal medications do decrease the probability of disease transmission to another person.

Chloroquine phosphate (Aralen) is one of the older drugs still used, and along with its sister medication, hydroxychloroquine sulfate (Plaquenil), is used in the prevention and treatment of malaria. These blood schizonticides are active against all Plasmodium species and have gametocidal activity against P. vivax, P. ovale, P. malariae, and P. knowlesi. These medications are no longer recommended for prophylaxis against P. falciparum (except in some parts of Central America), but can be used to prevent P. vivax infections. Chloroquine remains the treatment of choice for all susceptible Plasmodium strains; however, growing resistance limits its worldwide use, especially in malaria-endemic areas. It is safe to use in children as well as pregnant women. Response to treatment in pregnant women should be monitored closely, especially during second and third trimesters where serum drug concentrations may be lower. Major side effects include gastrointestinal (GI) upset, headache, dizziness, insomnia, vision changes, and pruritus. Long-term use can lead to ototoxicity, retinopathy, and peripheral neuropathy.

Atovaquone/proguanil (Malarone) is a combination drug effective against both blood and tissue schizonts. The combination is indicated for malaria prophylaxis in all areas and may be used for treatment of uncomplicated chloroquine-resistant malarial infections in travelers outside endemic areas or for combination treatment with artesunate10 or primaquine.1 It is seldom used in endemic areas due to emergence of resistance to the atovaquone component. The medication is considered safe in children weighing more than 5 kg per WHO (U.S. Food & Drug Administration [FDA] sets 11 kg as the weight minimum). WHO does regard the drug as safe during pregnancy due to no evidence of adverse effects associated with its use in pregnant women. The combination medication is generally well tolerated.

Headache, cough, and GI upset are the most frequent side effects in both adults and children. Rarely, dizziness, oral ulcerations, and elevated liver function study results can occur. It is contraindicated in those with severe renal impairment due to increased pancytopenia risk.

Artemisinin derivatives are plant-based compounds derived from the Chinese quinghaosu plant (Artemisia annua) whose components are active against blood schizonts and gametocytes. They also lead to much shorter parasite clearance times than other treatments.

Artemisinin and its derivatives (artesunate,10 artemether,2 and dihydroartemisinin2) are highly effective at treating uncomplicated and severe P. falciparum infections and preparations are available in oral, rectal, and intravenous formulations. Artemisinin-based combination therapies (ACTs) are increasingly considered standard of care for treatment of uncomplicated falciparum malaria in malaria- endemic areas.

ACT involves administering a combination drug over at least 3 days (7 days for Southeast Asia P. falciparum), which allows for more effective blood schizonticidal activity since the individual components have different actions and targets, as well as reducing potential selection for drug-resistant parasites. Currently five ACT options are approved by stringent regulatory authorities or the WHO: artemether + lumefantrine (Coartem; the only FDA-approved treatment), artesunate + amodiaquine (Coarsucam,2 European Medicines Agency-approved), artesunate + mefloquine (Artequin,2 WHO prequalified), artesunate + sulfadoxine-pyrimethamine (Arsuamoon2 + Fansidar,2 WHO prequalified), and dihydroartemisinin + piperaquine (Eurartesim,2 European Medicines

Agency-approved). Cure rates for all of these preparations exceed 95% based on clinical trial data.

Serious side effects from ACTs have not been reported in humans, but they are still not recommended during the first trimester of pregnancy due to lack of definitive safety data. Generally well- tolerated, common side effects include GI upset, dizziness, headache, neutropenia, and elevated liver enzymes. Although there are minor differences in the oral absorption, bioavailability, and tolerability of the different artemisinin derivatives, there is no evidence that these differences are clinically significant in currently available formulations.

For severe malaria, though artemisinin derivatives may be used alone to initiate therapy (i.e., IV artesunate10), another antimalarial medication with a different mode of action should be added as soon as possible. Parenteral artesunate has been available in the United States since 2007 under an investigational protocol. The CDC will provide it to hospitals upon request and on an emergency basis when a patient has severe malaria, a high parasite burden, inability to take oral medicines, lack of access to or failure of IV quinidine, or a contraindication to using quinidine. To enroll a patient in the protocol, clinicians should not hesitate to contact the CDC’s Malaria Hotline (770-488-7788 or toll-free at 855-856-4713) from 9 am to 5 pm Eastern Time, or outside of regular hours, physicians should call 770-488-7100 and request the CDC Malaria Branch’s on-call physician.

Quinine sulfate (Qualaquin) and quinidine gluconate (parenteral form) are blood schizonticides effective at killing erythrocytic stages of all Plasmodium species, and show gametocidal activity against P. vivax, P. ovale, and P. malariae. Currently, IV quinidine is the only FDA-approved treatment for severe malaria in the United States.

Quinine may be used in the treatment of uncomplicated malaria, particularly during the first trimester of pregnancy, or in cases when an effective ACT is not available. Quinine has a narrow therapeutic index and many potential side effects. Potential cardiotoxic effects include conduction disturbances like QT prolongation, angina, and hypotension leading to cardiac arrest. It is, therefore, recommended that IV quinidine be administered under close telemetry monitoring.

More common side effects include symptoms of tinnitus, hearing impairment, nausea, headache, dizziness, dysphoria, and sometimes disturbed vision. More severe issues at higher required doses or increased treatment duration include vertigo, vomiting, diarrhea, and marked auditory and visual loss. An important side effect of quinine seen mostly in children, pregnant women, and the elderly is hyperinsulinemic hypoglycemia. Treatment for major side effects is mostly supportive, with particular attention to maintenance of blood pressure, glucose and renal function and to treating any arrhythmias. For infection acquired outside of Southeast Asia, treatment course with quinidine may be shortened from 7 to 3 days when combining treatment with doxycycline,1 tetracycline,1 or clindamycin.1

Tetracyclines (i.e., doxycycline and tetracycline) are blood schizonticides effective against the erythrocytic stages of all Plasmodium. Doxycycline (Vibramycin) is effective in the prophylaxis against P. falciparum, including chloroquine- and mefloquine-resistant strains. Tetracyclines may be combined with quinine or quinidine to treat chloroquine-resistant P. falciparum and P. vivax infections. They should never be used as monotherapy and both are contraindicated in pregnancy and in children less than 8 years old due to possible interference with bone growth. Common side effects for these medications are GI upset, which can be lessened by ensuring it is taken with food, dry mouth, stomatitis, sun hypersensitivity, candida vaginitis, dysphagia, and esophageal irritation. To reduce esophageal problems, doxycycline should always be administered with a full glass of water.

Clindamycin (Cleocin)1 is another blood schizonticide of all Plasmodium species. It may be used in combination therapy with artesunate or quinine for severe or uncomplicated malaria, but never as monotherapy. Clindamycin is often used when tetracyclines are contraindicated. It is generally well tolerated in its oral form. Major side effects include GI upset (especially diarrhea) and skin rashes.

Close monitoring is recommended in the elderly, neonates, and individuals with liver disease.

Mefloquine (Lariam) is a long-acting blood schizonticide effective at killing the erythrocytic stages of all Plasmodium species. Structurally related to quinine, it is used as prophylaxis against malaria caused by all Plasmodium species, and also combined with artesunate to treat P. falciparum infections. It is generally thought to be safe during pregnancy, and is well tolerated when given in combination with artesunate for the treatment of uncomplicated P. falciparum malaria. It is also effective as a once-weekly prophylactic medication. Though generally well-tolerated, common side effects include GI disturbances, anxiety, irritability, dizziness, paranoia, depression, hallucinations, and sometimes violence in patients who were treated for malaria or taking mefloquine for long-term prophylaxis. Side effects frequently abate once the medication is discontinued. Use of mefloquine for malaria prophylaxis is not recommended for those for whom sudden dizziness or confusion could be hazardous, especially pilots and drivers. Travelers taking mefloquine are advised to stop taking the medication should any neurologic symptoms develop. Mefloquine is contraindicated to use as follow-up therapy for patients after cerebral malaria and should also not be used for prophylaxis in patients with known cardiac conduction disorders, epilepsy, depression or anxiety, psychosis, schizophrenia, or other major psychiatric disorder. It should also never be used in combination with quinine or quinidine.

Due to the neuropsychiatric side effects of mefloquine, it is often not considered as first-line for prophylaxis or treatment.

Primaquine sulfate is effective at eradicating both the exoerythrocytic forms (hypnozoites) and the sexual stages of malaria parasites (gametocytes). It is used for radical cure of P. vivax and P. ovale1 malaria, primary prophylaxis for destinations where P. vivax is the main species, as well as for terminal prophylaxis (presumptive antirelapse therapy) targeting parasites that may remain dormant in the liver, in P. vivax and P. ovale infections. Both antirelapse therapy and radical cure treatment should be for 14 days—started the first day the patient has left the malarious area—and used in conjunction with a malaria schizonticide. Often it is well tolerated but may cause GI upset that improves when taking the medication with food. Most importantly, primaquine can cause hemolytic anemia in individuals who are deficient in glucose-6-phosphate dehydrogenase (G6PD), so normal G6PD levels must be ensured before starting primaquine.

Patients should discontinue primaquine if they pass red or black urine, or have symptomatic anemia. Primaquine is also contraindicated during pregnancy and during breastfeeding unless the infant’s G6PD status is known.

In addition to the medications mentioned above, several other antimalarials may be encountered in malaria-endemic areas that are not approved for use by the FDA due to poor efficacy or unwelcome side-effect profiles (e.g., individual components of ACTs like amodiaquine [Camoquin]2 and sulfadoxine-pyrimethamine,2 or halofantrine [Halfan]2). Therefore, travelers and physicians counseling patients should be aware of those medications approved by the regulatory authorities in their respective countries.

For travelers, authenticity of medications must also be ensured.

Unfortunately, the quality of medications commercially available in malaria-endemic countries can vary greatly. While appearing to be genuine, counterfeit medications may have little to no active ingredient or may contain ingredients not indicated on their label. If travelers have to purchase medications outside of their home country, they need to scrutinize medication packaging for printing errors and signs of tampering. The color, consistency, odor, and taste of the medication may also alert one to counterfeit medication. The Medicines Quality Database (MQDB) through the U.S. Pharmacopeial Convention is one resource available to investigate medicine quality in countries throughout the world (see http://www.usp.org/global- health-programs/promoting-quality-medicines-pqmusaid/medicines- quality-database-mqdb).

Treatment

Unless there is clinical concern for severe disease or prompt laboratory diagnosis is unobtainable, malaria treatment should be initiated once the diagnosis is established by laboratory testing. Upon confirmation of the diagnosis, treatment management should be based on the identity of infecting Plasmodium species, the patient’s clinical status and level of parasitemia, prior use of antimalarials, and the geographic area where the infection was likely acquired.

If identification reveals the presence of P. falciparum malaria or Plasmodium species remains uncertain, patients should be hospitalized and monitored closely for possible development of severe malaria symptoms and complications. When clinical and laboratory data support low severity, it is safe to treat patients in the outpatient setting with oral therapy. Should symptoms become more severe, though, as described below, the patient should be started on parenteral therapy and admitted to intensive care. As a default, clinicians should always treat those with malaria where the infecting species is unknown as if they had a chloroquine-resistant P. falciparum infection until proven otherwise. Routine serial blood monitoring for parasite density using blood smears will also help modify therapy as needed. Clinicians must be mindful, though, that increases in parasite density within the first 24 hours of treatment may represent normal release of parasite from RBCs and not worsening infection, especially when the patient’s symptoms are improving with current therapy.

Monitoring should continue until blood smears are negative and alternative treatments need to be considered if the patient’s symptoms are not improving and parasite density is not decreasing.

Detailed treatment information regarding dosing and frequency may be found in Tables 1–3.

Chloroquine-Sensitive Plasmodium (P. falciparum, P. knowlesi, P. malariae, P. ovale, and P. vivax)

Oral chloroquine phosphate is the recommended treatment for all sensitive malaria strains. Confirmed infections with P. ovale, P. malariae, and P. knowlesi are generally sensitive to chloroquine and treatment should not be delayed, especially for P. knowlesi, which has the capacity to increase parasitemia rapidly and become very severe. For P. falciparum and vivax infections, chloroquine may be indicated if the confirmed geographic area of exposure has no known chloroquine resistance. In addition, for all P. ovale and vivax infections, patients with normal G6PD activity require primaquine therapy for 14 days to reduce potential relapse.

Chloroquine-Resistant P. falciparum

In the case of P. falciparum infection from areas with known chloroquine resistance, several options are available. Where available, artemisinin-based combination therapies (ACTs) are considered the standard of care, but other agents may also be used (see Table 3). In the United States four different treatment options are available: atovaquone-proguanil, artemether-lumefantrine, quinine sulfate combined with doxycycline,1 tetracycline,1 or clindamycin,1 or mefloquine. Due to neuropsychiatric side effects, mefloquin should be considered only when other options are not available or contraindicated. It should also not be used when the P. falciparum strain was acquired in Southeast Asia due to increased resistance to mefloquine in that region.

Table 3

Artemisinin Combination Therapies (ACTs)*1

Medication                                                     Adult and Pediatric Dosing (by body weight)
Artemether  + lumefantrine2,3 Artemether + lumefantrine (mg) bid for 3 days: 5 to < 15 kg: 20 + 120

15 to < 25 kg: 40 + 240

25 to < 35 kg: 60 + 360

> 35 kg: 80 + 480

Artesunate  + amodiaquine4,† Artesunate + amodiaquine (mg) daily for 3 days: 4.5 to < 9 kg: 25 + 67.5

9 to < 18 kg: 50 + 135

18 to < 36 kg: 100 + 270

> 36 kg: 200 + 540

Artesunate + mefloquine5,† Artesunate + mefloquine (mg) daily for 3 days: 5 to < 9 kg: 25 + 55

9 to < 18 kg: 50 + 110

18 to < 30 kg: 100 + 220

> 30 kg: 200 + 440

Artesunate  + sulfadoxine/pyrimethamine6,† Artesunate (mg) daily for 3 days + sulfadoxine/pyrimethamine (mg) single dose day 1:

5 to < 10 kg: 25 + 250/12.5

10 to < 25 kg: 50 + 500/25

25 to < 50 kg: 100 + 1000/50

> 50 kg: 200 + 1500/75

Dihydroartemesinin  + piperaquine7,† Dihydroartemesinin + piperaquine (mg) daily for 3 days: 5 to < 8 kg: 20 + 160

8 to < 11 kg: 30 + 240

11 to < 17 kg: 40 + 320

17 to < 25 kg: 60 + 480

25 to < 36 kg: 80 + 640

36 to < 60 kg: 120 + 960

60 to < 80 kg: 160 + 1280

> 80 kg: 200 + 1600

Lack of resolution of malaria symptoms or recurrence within 4 weeks of treatment are considered treatment failures and a different ACT should be  tried.

*  Recommended therapies per WHO.

†  Not available in the United States.

1 Artemisinins and their partner medicines above should not be used alone for treatment, only in a combination.

2  Only ACT that is approved for use by U.S.  FDA.

3  Absorption of lumefantrine is enhanced by coadministration with  fat.

4 In patients with HIV, concomitant use of zidovudine, efavirenz, or cotrimoxazole should be avoided.

5 Contraindicated in people allergic to mefloquine or related compounds (quinine, quinidine) and in people with depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Not recommended for persons with cardiac conduction  abnormalities.

6  Only ACT that it is not available as a fixed-dose  combination.

7 High-fat meals should be avoided as they significantly accelerate the absorption of piperaquine.

Chloroquine-Resistant P. vivax

Though mostly sensitive to chloroquine, P. vivax infections acquired in Indonesia and Papua New Guinea often show resistance. Common treatment regimens for chloroquine-resistant strains include atovaquone-proguanil, quinine sulfate1 combined with doxycycline1 or tetracycline,1 or mefloquine. There is also very good evidence to support using ACTs, where available, for treatment of both chloroquine-resistant and chloroquine-sensitive strains. As mentioned before, all P. vivax-infected patients should also receive primaquine therapy for 14 days to eradicate any hypnozoite forms.

Severe Malaria

Severe disease is likely in those patients with a positive blood smear or a concerning exposure history who also exhibit at least one of the following: impaired consciousness or coma, severe normocytic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, seizures, and parasitemia of over 5%. Mortality risk increases with increasing numbers of the signs/symptoms especially when signs of acidosis, vital organ dysfunction, or high parasite count are present. Immediate

point of care testing, where available, should always include measures of hematocrit, parasite count, and blood glucose. The mortality rate for patients with untreated severe malaria (particularly cerebral malaria) is almost 100%. Fortunately, with prompt effective treatment and supportive care, mortality may fall to 10%.

Any patient considered to be at increased risk should receive the highest level of care available (e.g., intensive care unit) and parenteral antimalarial drug treatment (artesunate or quinidine) should be started without delay. Adults and children with severe malaria (including infants, pregnant women in all trimesters, and lactating women) should be treated with IV or IM artesunate for at least 24 hours where available. As soon as oral therapy can be tolerated after the initial 24 hours of parenteral therapy, treatment with 3 days of an ACT should continue (7 days if likely acquired from Southeast Asia). When IM and IV forms are not available, rectal administration of artesunate (10 mg/kg body weight) in young children (< 6 years) in prereferral settings has also proven to be a life-saving adjuvant before arrival at a facility for further care. When quinidine is used, as it most frequently would be in the United States, parenteral therapy (to include IV doxycycline1 or clindamycin1) should be given for a minimum of 24 hours and then switched to oral treatment once tolerated after that. When an ACT is not available for follow-on treatment, artesunate + clindamycin,1 artesunate + doxycycline,1 quinine + clindamycin, quinine + doxycycline, or atovaquone- proguanil can be used.

Regarding general monitoring and supportive care, fluid requirements should be assessed individually and signs of shock quickly addressed. Adults with severe malaria are very vulnerable to fluid overload and pulmonary edema, while children are more likely to be dehydrated. Severe malaria can be associated with rapid development of anemia, as erythrocytes are hemolyzed and/or removed from the circulation by the spleen. Ideally, fresh, cross- matched blood should be available for transfusion when hematocrit levels fall to below 15% in children or 20% in adults. Cardiac monitoring is also essential, especially when using quinidine, which is known to cause conduction abnormalities at the loading dosages required for initial treatment. Of note, after artesunate treatment in hyperparasitemic nonimmune travelers, it is common for delayed hemolysis to occur after a week, and so such patients need to be followed for these changes. Given the potential clinical overlap between malaria and sepsis, especially in children, blood cultures should always be taken and empiric antibiotic treatment should be started along with antimalarial therapy until bacterial infection can be ruled out. Additionally, though incorporated into some older recommendations, both the CDC and WHO no longer recommend using exchange transfusions or prophylactic anticonvulsants as adjunct treatment in severe malaria as the data do not support any mortality benefit.

Clinicians with questions about effective treatment (or diagnosis) should consult with an infectious disease specialist or a physician with specialized training in travel or tropical medicine. If no such local avenues are available, clinicians should not hesitate to contact the CDC’s Malaria Hotline (referenced previously).

Treatment in Pregnancy

Pregnancy complicates the treatment strategy as it affects both the mother and her fetus. Infections, especially with P. falciparum, can increase susceptibility to severe disease and risk of developing anemia, while increasing fetal risk for low birth weight and prematurity in addition to miscarriage. Symptoms of pregnant patients may also be more muted in high-transmission areas than for those in low-transmission areas despite the adverse effects on fetal growth. Congenital malaria must be considered when infants born to mothers with acute malaria infection show signs of fever, anemia, or failure to thrive during the first few months of birth. In most cases, treatment of newborns or infants should proceed if symptoms are present and infection status is confirmed. While remaining vigilant, providers must also educate mothers about symptoms and the importance of quick follow-up should they develop. Of note, congenitally acquired malaria in infants does not involve a liver stage so primaquine is not needed.

As pregnant women are largely excluded from many clinical trials, safety and efficacy data are lacking for them, especially during the first trimester. Nevertheless, a number of recommendations have been made from available data regarding treatment of pregnant women.

During the first trimester, current guidelines list chloroquine, quinine, clindamycin, and proguanil2 as safe. Additionally, review of available data has moved the FDA to list mefloquine as a pregnancy Category B medication showing no increase in birth defects or fetal loss throughout pregnancy. Though some prospective data do support its use early in pregnancy, WHO only recommends ACTs in the first trimester if it is the only treatment available, in cases of severe malaria where IV artesunate is indicated, if treatment with quinine plus clindamycin1 fails, or if uncertainty of compliance with a 7-day treatment exists (quinine is only needed for 3 days if infection was acquired outside Southeast Asia).

After the first trimester, several artemisinin derivatives, alone or in combination with other antimalarials, have been evaluated as safe and efficacious in second and third trimester pregnancy. Therefore, the WHO recommends that ACTs be used during the second and third trimester of pregnancy where the choice of ACT is governed by local efficacy (most recommended are artemether-lumefantrine, artesunate- amodiaquine,2 artesunate-mefloquine,2 and artesunate-sulfadoxine- pyrimethamine2). For those with P. malariae, P. vivax, P. ovale, or chloroquine-sensitive P. falciparum malaria, chloroquine treatment, the same as for nonpregnant patients, should be instituted.

Primaquine phosphate for treatment of P. vivax or P. ovale1 hypnozoites should not be given during pregnancy. If P. vivax or P. ovale infections are confirmed, pregnant patients should be maintained on weekly chloroquine prophylaxis for the duration of their pregnancy, 300 mg base (= 500 mg salt) orally once per week. Primaquine therapy can be initiated after delivery in those patients with known normal G6PD levels. Due to possible breast milk excretion of primaquine, it should not be used by nursing women unless infants have known normal G6PD levels.

For severe malaria cases, parenteral antimalarial drugs should be given to pregnant women in full doses without delay regardless of trimester. IM artemether may be used if artesunate is unavailable; otherwise parenteral quinine should be started immediately until artesunate is obtained. Pulmonary edema and hypoglycemia are commonly seen, the latter especially when quinine is used, so patients should be monitored carefully.

Treatment of the Pediatric Patient

Delay in treating P. falciparum malaria in infants and young children can have fatal consequences, particularly for more severe infections. The vast majority of malaria cases and deaths in the world, especially Africa, occur in young children. Fortunately, many antimalarial drugs have included children in clinical trials. Therefore, treatment recommendations are not just based on extrapolated data.

Recommendations are consistent with those for adult patients but require appropriate dosage changes based on patient weight, and the dosage should never exceed the adult dose.

Chloroquine may be used for any chloroquine-sensitive malaria strains and, where available, artemisinin derivatives (artemether- lumefantrine being the most studied) are considered safe and very well tolerated and represent first-line treatment for chloroquine- resistant P. falciparum. Alternatively, quinine sulfate and quinidine may be given in combination with clindamycin1 in those areas with poorer access to artemisinin derivatives. Atovaquone-proguanil may also be considered in this group as well as mefloquine, but only if no other options are available for the latter. Of note, for small infants weighing less than 5 kg, the WHO does recommend treatment with ACT at the same target dose as for children weighing 5 kg or more.

No modifications are currently warranted in those suffering malnutrition; however, their response to treatment should be monitored closely. Regarding treatment combinations with tetracycline1 or doxycycline,1 these drugs should only be used with extreme prejudice in those under 8 years of age and only when other treatments are not available or not tolerated and the benefits are judged to outweigh the risks. Also, primaquine should only be given to those children with known normal levels of G6PD.

Prevention

Preventive measures are important to ensure protection against malaria. Limiting exposure to the mosquito disease vector, Anopheles species, as well as taking appropriate drug prophylaxis measures are key components in preventing malaria in both travelers and those living in malaria-endemic locations.

The Anopheles mosquito is primarily a nocturnal feeder so protecting oneself during the periods from dusk to dawn is essential to avoid possible infection. In this effort, remaining indoors or within well-screened areas, wearing clothing of a tight mesh that covers most of the body, using bed nets, ideally treated with insecticide, and using insecticide sprays on clothing and/or the body especially during evening and nighttime hours are all key. Spraying indoor areas with insecticides also adds protection. Certainly some of the malaria mortality reductions seen worldwide directly relate to the efforts in malaria-endemic areas to increase access to insecticide-treated bed nets and improved efforts in indoor residual spraying.

Several commercial insecticides and insect repellents are available. For clothing and bed nets, pyrethroids (i.e., permethrin) are typically used and fairly effective at protecting against mosquitoes, though some reports warn of developing resistance. Using insect repellents, too, greatly minimizes Anopheles exposure. Currently, DEET (diethylmethyl-toluamide) is most frequently used and is known to be safe for all age groups including infants down to 2 months old.

Concentrations above 25% are often recommended and individuals should remember to reapply repellent at a minimum of every 8 hours. In addition to DEET, picaradin (e.g., Natrapel 8 Hour Insect Repellent and Sawyer Premium 20% Picaradin Spray) products and IR3535 or ethyl butylacetylamino-propionate (e.g., Avon Skin-So-Soft Bug Guard Plus and Sawyer Insect and Sun Spray) are also recommended by both the CDC and WHO. Meanwhile, oil of lemon eucalyptus (e.g., Repel and Off!) is only recommended by the CDC for those repellents receiving U.S. Environmental Protection Agency approval. Travelers should always remember that when using topical skin repellents, they should be applied after any sunscreen is applied to exposed skin surfaces.

Chemoprophylaxis measures are also an important preventive medicine concern. For travelers and at-risk groups living in endemic areas, there are a number of recommended chemoprophylaxis regimens currently available (see Table 4). Key to all of these is taking an agent before, during, and after travel to a malaria-endemic area.

One must ensure that the prophylactic agent is present in the bloodstream before any potential exposure. When in doubt, clinicians may use the CDC’s online interactive malaria map or Malaria-by- Country tables (both referenced previously) to quickly view the types of Plasmodium present and resistance characteristics found in the patient’s area of travel. In combination with the patient’s individual medical history, age, medications, and travel duration, this information can be used by the clinician to treat the patient appropriately. Additionally, pregnant women who choose to travel to a malaria-endemic area must be aware that malaria severity is often increased during pregnancy. Personal protective measures and steadfast use of chemoprophylaxis (e.g., mefloquine or hydroxychloroquine) are key.

Table 4

Recommendations for Malaria Chemoprophylaxis

 

1 Contraindicated in severe renal impairment (creatinine clearance < 30 mL/min). Not recommended for children < 5 kg and pregnant  women.

2  Contraindicated in children < 8 years of age and pregnant  women.

3 Contraindicated in people allergic to mefloquine or related compounds (quinine, quinidine) and in people with depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures. Not recommended for persons with cardiac conduction  abnormalities.

4 Currently Category B in pregnancy (FDA), recommended as option for treatment and prophylaxis in all trimesters.

5 Contraindicated in G6PD deficiency. Also contraindicated during pregnancy and lactation, unless infant has normal G6PD level.

6  Dosing based on fixed-dose combination tablets of 500 mg sulfadoxine/25  mg pyrimethamine.

7  Not FDA approved for this indication.

8  Exceeds dosage recommended by the  manufacturer.

9  Not available in the United States.

The WHO does encourage intermittent preventive treatment with sulfadoxine-pyrimethamine (SP-IPT)2 for pregnant women living in endemic areas and for infants. For pregnant women during their first or second pregnancy living in endemic areas in Africa with moderate to high P. falciparum transmission, intermittent pregnancy treatment of malaria with SP-IPTp is recommended. Dosing should start in the second trimester and doses should be given at each antenatal visit at least 1 month apart. In addition, as a prophylactic in pediatric patients living in areas of higher malaria transmission in Africa, the WHO recommends providing intermittent preventive treatment with SP- IPTi to infants (< 12 months of age) at the time of the second and third rounds of vaccination against diphtheria, tetanus, and pertussis (DTP) and vaccination against measles. Similarly, in areas with seasonal malaria transmission in the sub-Sahel region of Africa, seasonal malaria chemoprevention with monthly amodiaquine2 + SP is recommended for all children less than 6 years old during each transmission season.

There is no malaria vaccine currently on the market, but RTS,S/AS01 is a candidate vaccine with somewhat promising Phase III trial data in pediatric patients. Consisting of three initial monthly doses and a booster 18 months after the third dose, over a 48-month period it showed efficacy against clinical malaria of up to 39% and against severe malaria of 31.5%. This represented an estimated number of averted clinical malaria cases in pediatric patients on the order of 1774 per 1000 children in those receiving the booster dose.

Although certainly representing another worthwhile tool in combating malaria, the extent to which the protection demonstrated can be replicated in the context of a routine health-care system remains uncertain. Similarly, in an effort to combat P. vivax infection, Phase III data on tafenoquine, a long-acting primaquine derivative, have shown good activity against all stages of the P. vivax life cycle and may be developed for the radical cure of acute P. vivax malaria in combination with chloroquine. It may also potentially treat P. vivax hypnozoites with a single dose instead of the current 14-day protocol for primaquine.

Note

The views expressed here are those of the authors and do not reflect the official policy or position of the U.S. Air Force, the Department of Defense, or the U.S. government.

References

1.     Abba K., Kirkham A.J., Olliaro P.L., et al. Rapid diagnostic tests for diagnosing uncomplicated non-falciparum or Plasmodium vivax malaria in endemic countries. (online) Cochrane Database Syst Rev. 2014. ;2014(12):CD011431. Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD011431 (accessed 14.11.15).

2.    Centers for Disease Control and Prevention. Treatment of Malaria (guidelines for clinicians). Available at: http://www.cdc.gov/malaria/resources/pdf/clinicalguidance.pd 2013a (accessed 14.11.15).

3.     Centers for Disease Control and Prevention. Guidelines for Malaria treatment in the United States. Available at: http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf. 2013b (accessed 14.11.15).

4.    Cullen K.A., Arguin P.M. Surveillance summaries: malaria surveillance—United States, 2012. Morb Mortal Wkly Rep. 2014;63(SS12):1.

5.     Navy and Marine Corps Public Health Center. Pocket Guide to Malaria Prevention and Control. Portsmouth, VA: US Navy and Marine Corps Public Health Center; 2011.

6.      RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomized, controlled trial. Lancet. 2015;386:31.

7.    Visser B.J., van Vugt M., Grobusch M.P. Malaria: an update on current chemotherapy. Expert Opin Pharmacother. 2014;15:2219.

8.    Wells T.N.C., van Huijsduijnen R.H., Van Voorhis W.C. Malaria medicines: a glass half full? Nat Rev Drug Discov. 2015;14:424. White N.J., Pukrittayakamee S., Hien T.T., et al. Malaria. Lancet. 2014;383:723.

9.       World Health Organization. Guidelines for the treatment of malaria. 3rd ed. Geneva: WHO; 2015a.

10.       World Health Organization. World Malaria Report – 2015. Geneva: WHO; 2015b.

2  Not available in the United  States.

2  Not available in the United  States.

10  Available in the United States from the Centers for Disease Control and   Prevention.

1 Not FDA approved for this indication. 1

Not FDA approved for this indication. 1

Not FDA approved for this indication. 2

Not available in the United  States.

1  Not FDA approved for this  indication.

1  Not FDA approved for this  indication.

2  Not available in the United  States.

1 Not FDA approved for this indication. 1

 Not FDA approved for this indication. 2

Not available in the United  States.

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