Introduction
Background
Malaria is the most deadly vector-borne disease in the world. Although typically an illness of tropical regions of the world, more than 1500 cases (nearly all foreign-originating) are diagnosed in the US each year. In some parts of the world, malaria is known as paludism (paludismo). Blackwater fever refers to the dark urine sometimes seen as a result of severe red blood cell hemolysis from malaria.
At least 10 of the more than 200 parasitic protozoa species of the genus Plasmodium (Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum), and Plasmodium knowlesi, cause human malaria. P falciparum causes the most severe morbidity and mortality.
Malaria is primarily transmitted through the bite of an infected female Anopheles species mosquito. Malaria also can be transmitted via a blood transfusion or congenitally between mother and fetus, although these forms of infection are rare.
At risk for contraction of malaria are persons living in or traveling to areas of Central America, South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Of these areas, sub-Saharan Africa has the highest occurrence of P falciparum transmission to travelers from the United States.
Pathophysiology
The vector, the Anopheles species mosquito, passes plasmodia, which are contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (RBCs) and feed on the hemoglobin and other proteins within the cells. One brood of parasites becomes dominant and is responsible for the synchronous nature of the clinical symptoms of malaria. Malaria-carrying female Anopheles species mosquitoes tend to bite only between dusk and dawn.
Schema of the life cycle of malaria. Image courtesy of the Centers for Disease Control and Prevention.
P vivax and P ovale may produce a dormant form that persists in the liver of infected individuals and emerges at a later time. Therefore, infection by these species requires treatment to kill any dormant protozoan as well as the actively infecting organisms. This dormant infection is caused by the hypnozoite phase of the life cycle, which involves a quiescent liver phase, which is not typically eradicated by normal courses of antimalarials and requires treatment with primaquine to prevent further episodes of disease.
Malaria-causing Plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment termed hemozoin (see Media file 3).
An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other RBCs. Notice the darkened central portion of the cell; this is hemozoin, or malaria pigment, which is a paracrystalline precipitate formed when heme polymerase reacts with the potentially toxic heme stored within the erythrocyte. When treated with chloroquine, the enzyme heme polymerase is inhibited, leading to the heme-induced demise of non–chloroquine-resistant merozoites.
The morbidity and mortality caused by P falciparum are increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P falciparum and its ability to cytoadhere. When an RBC becomes infected with P falciparum, it produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, leading to much of the damage incurred by the parasite. Furthermore, P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). By contrast, P vivax and P ovale only infect young RBCs and thus have a relatively limited parasitemia (usually <2%).
Frequency
United States
Although cases of malaria occur in some areas of the United States in people who have not traveled outside the country and have no other known risk factors, malaria ceased to be an endemic disease to the country as of 1947. Most cases of malaria reported by those living in the United States are associated with recent travel to an endemic area. Malaria may also be transmitted at birth or trans-placentally. Rarely, malaria is transmitted through blood transfusion, needle-sharing, or organ transplant.
Travelers to forested areas of Southeast Asia and South America have become infected by Plasmodium knowlesi, a dangerous species normally found only in long-tailed and pigtail macaque monkeys (Macaca fascicularis , Macaca nemestrina). This species can cause severe illness and death in people, but, under the microscope, the parasite looks similar to the more benign P malariae and has sometimes been misdiagnosed. As P malariae infection is typically relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographical areas with microscopic evidence of P malariae infection who are severely ill. Diagnosis may be confirmed via polymerase chain reaction (PCR) methods.
International
Malaria remains an enormous international medical issue, with an estimated 300-500 million cases occurring annually.1 It is most prevalent in rural tropical areas below elevations of 1000 m (3282 ft) but is not limited to these climates. P falciparum is found mostly in the tropics and accounts for about 50% of cases and 95% of malarial deaths worldwide. P vivax is distributed more widely than P falciparum, but it causes less morbidity and mortality; however, both P vivax and P ovale can establish a hypnozoite phase in the liver, resulting in latent infection.
HIV and malaria co-infection is a significant problem across Asia and sub-Saharan Africa where both diseases may be relatively common. Evidence suggests that malaria and HIV co-infection can lead to worse clinical outcomes in both disease processes, with malarial infections being more severe in HIV-infected patients, and HIV replication increasing in malaria infection.
Mortality/Morbidity
- Internationally, as many as 2 million deaths occur annually. Of these deaths, the overwhelming majority is among children aged 5 years or younger, and 80-90% of the deaths each year are in rural sub-Saharan Africa.1 Malaria is the world’s fourth leading cause of death in children younger than 5 years, accounting for the majority of malaria-related deaths.
- Malaria is preventable and treatable. However, the lack of prevention and treatment due to poverty, war, and other economic and social instabilities in endemic areas results in millions of deaths each year.
Race
The sickle cell trait (hemoglobin S), thalassemias, hemoglobin C, or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are protective against death from P falciparum malaria, with the former being relatively more protective than the latter three. Individuals with hemoglobin E may be protected against P vivax infection. Individuals heterozygotic for RBC band 3 ovalocytosis are at reduced risk of infection with P falciparum, Plasmodium knowlesi and, especially, P vivax malaria. West African populations lacking RBC Duffy antigen are completely refractory to infection by P vivax.
Persons living in areas of malaria endemicity may develop partial immunity to infection with time and repeated exposure. This limited immunity reduces the frequency of symptomatic malaria and also reduces the severity of infection. Immunity to malaria infection can be lost with long periods of time spent away from endemic areas with limited exposure. As a result, those individuals born in malaria-endemic regions who move abroad for work or study and then return home may be at increased risk for developing severe malaria and complications of infection.
Sex
Males and females are affected equally. However, malaria may be devastating in pregnancy to both the mother and the fetus. P falciparum is the primary species responsible for increased morbidity and mortality in pregnancy. The prevalence of malaria is higher in primigravidas than in nonpregnant women or multigravidas. Maternal complications are thought to be mediated by pregnancy associated decreases in immune function as well as placental sequestration of (P falciparum) parasites. Anemia from malaria can be more severe in pregnant women. Fetal complications include death, premature birth, anemia, and low birth weight.
Age
- All ages are affected by malaria.
- Mortality is very high in children younger than 5 years.
Clinical
History
Most patients live in or have recently traveled to an endemic area; however, a few cases are reported each year in which the patient had no history of such travel (eg, airport malaria, from imported mosquitoes). Malaria may present over 1 year after travel to an endemic area. Previously infected patients may develop relapsing malaria, a recurrence of the disease after it has been apparently cured; this form is caused by reactivation of hypnozoites (dormant liver-stage parasites) in P vivax and P ovale infections.
- Determine the patient's immune status, age, allergies, other medical conditions, other medications, and pregnancy status.
- The patient usually remains asymptomatic for a week or more after the infecting mosquito bite.
- Clinical symptoms 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 fever spikes a day.
- Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.
• Less common symptoms include the following:
- Anorexia and lethargy
- Nausea and vomiting
- Diarrhea
- Headache
- Jaundice
Physical
- Physical signs that may be noted with malaria include the following:
- Tachycardia
- Fever
- Hypotension
- Signs of anemia
- Splenomegaly
- Icterus
Causes
- Malaria most often is caused by the bite of a female Anopheles species mosquito that is infected with species of the protozoan genus Plasmodium. The 5 most common species affecting humans are as follows:
- P vivax: If this kind of infection goes untreated, it usually lasts for 2-3 months with diminishing frequency and intensity of paroxysms. Of patients infected with P vivax, 50% experience a relapse in a few weeks to 5 years after the initial illness. Splenic rupture may be associated with P vivax infection secondary to splenomegaly resulting from RBC sequestration. P vivax infects only immature RBCs, leading to limited parasitemia.
- P ovale: These infections are similar to P vivax infections, although they are usually less severe. P ovale infection often resolves without treatment. Similar to P vivax, P ovale infects only immature RBCs and parasitemia is usually less than that seen in P falciparum.
- P malariae: Those infected with this species of Plasmodium remain asymptomatic for a much longer period of time than those infected with P vivax or P ovale. Recrudescence is common in those infected with P malariae. It often is associated with a nephrotic syndrome, possibly resulting from deposition of antibody-antigen complex upon the glomeruli.
- P knowlesi: Autochthonous cases have been documented in Malaysian Borneo, Thailand, Myanmar, Singapore, and in the Philippines, and other neighboring countries. It is thought that simian malaria cases probably also occur in Central America and South America. Patients infected with this, or other simian species, should be treated as seriously as those infected with falciparum malaria, as P knowlesi may cause fatal disease.2
- P falciparum: The most malignant form of malaria is caused by this species. Infection with P falciparum is not limited to RBCs of a particular age and, hence, represents the highest level of parasitemia among the 5 Plasmodium species. This species also causes vascular obstruction due to its ability to adhere to endothelial cell walls. This property leads to most complications of P falciparum infection. P falciparum can cause cerebral malaria, pulmonary edema, rapidly developing anemia, and renal problems. Blackwater fever, is the darkening of the urine seen with severe RBC hemolysis resulting from high parasitemia, and is often a sign of impending renal failure and clinical decline.
- Other less common routes of infection are through blood transfusion and maternal-fetal transmission. When P vivax and P ovale are transmitted via blood, no latent hypnozoite phase occurs and treatment with primaquine is not necessary, as it is the sporozoites that form hypnozoites in infected hepatocytes.
Differential Diagnoses
Other Problems to Be Considered
African trypanosomiasis
Amebiasis and amebic liver abscess
Brucellosis
Cholera
Collagen vascular disease
Enteric fever
Epidemic or louse-borne typhus
Food-borne illness or toxin
Hodgkin disease
Relapsing fever
Poliomyelitis
Schistosomiasis (acute Katayama fever)
Seizure disorder
HIV infection
Workup
Laboratory Studies
- Helpful studies include a CBC, electrolyte panel, renal function tests, pregnancy test, urinalysis, free serum haptoglobin, urine and blood cultures, and thick and thin blood smears. For those patients who may receive quinine or primaquine, a G-6-PD test should be ordered. Lumbar puncture may be indicated in patients who have encephalopathy in which the diagnosis is not clear. Rapid HIV testing may also be indicated in select cases.
- Laboratory diagnosis in the ED may be limited in hospitals that do not have personnel who are well acquainted with malaria or special tests for rapid detection of the disease.
- The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria.3
Imaging Studies
- A chest radiography may be helpful if respiratory symptoms are present.
- If CNS symptoms are present, a CT scan of the head may be obtained once the patient is stable to evaluate evidence of cerebral edema or hemorrhage.
Other Tests
- 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 that species, a peripheral blood smear must be examined.
- Giemsa-stained thick and thin peripheral blood smears
- These smears are the criterion standard for malaria detection and should be sent to the laboratory immediately, since malaria is a potentially life-threatening infection.
- When reading the 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.
- 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 (QBC II System, Becton-Dickinson's Quantitative Buffy Coat [QBC] method). Fluorescent /ultraviolet tests may not yield speciation information.
- Polymerase chain reaction
- Polymerase chain reaction (PCR) is a very specific and sensitive test for determining if the species of Plasmodium are present in the blood of an infected individual. PCR is not usually available in most clinical situations.
- PCR is also very effective at detecting the Plasmodium species present in patients with parasitemias as low as 10 parasites/mL of blood.
- Rapid diagnostic tests (RDTs) examples include Para Sight-F test (Becton Dickinson Advanced Diagnostics), ICT Malaria P.f/P.v (Binax Inc), OptiMAL pLDH (DiaMed USA, LLC), Kat-Quick (Katmedical CC), and Rapimal MT Pf Dipstick (Cellabs Pty Ltd) (dipstick tests). Note: This list is not all-inclusive; research individual tests for comparative efficacy and cost.
- These tests are useful in detecting P falciparum infections, while some also may detect other plasmodia antigens. RDTs are based on antibody recognition of the histidine rich protein 2 (HRP-2) antigen of P falciparum and, in most cases, it has been found to be as specific as microscopy studies.4 A false-positive result may occur up to 2 weeks or more after treatment due to persistence of circulating antigens.
- Some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification.
- RDTs are not as effective when parasite levels are below 100 parasites/mL of blood, and the test rarely is negative in those with high parasitemias. For these reasons, always confirm RDT test results with a second type of screening test when possible.
- RDTs may not be available in the United States due to lack of FDA approval. The World Health Organization's Regional Office for the Western Pacific (WHO/WPRO) provides technical information, including a list of commercially available malaria RDTs, at Malaria Rapid Diagnostic Tests.
- In one study, RDTs were found to perform better than microscopy under routine conditions. RDTs performed by the health facility staff were 91.7% (95% confidence interval [CI], 80.8-100%) sensitive and 96.7% (95% CI, 92.8-100%) specific. Microscopy was 52.5% (95% CI, 33.2-71.9%) sensitive and 77% (95% CI, 67.9-86.2%) specific.5
Treatment
Emergency Department Care
- Assess airway, breathing, and circulation; intervene as necessary. Protective airway may be indicated in cases of severe central nervous system complications.
- If evidence of life-threatening hemolytic anemia is determined, establish large-bore intravenous (IV) lines, initiate fluid resuscitation, and administer transfusion of type-specific packed RBCs.
- Hyponatremia likely reflects continued oral hypotonic fluid intake in the setting of hypovolemia and requires no therapy beyond rehydration.6 Overly aggressive treatment of hyponatremia may lead to death.
- Consider exchange transfusion for life-threatening complications.
- Monitor and treat hypoglycemia, as needed.
- Search for any signs of microvascular malarial complications.
- Laboratory analysis is helpful, although it is not always readily available to determine Plasmodium species, level of drug resistance, and degree of parasitemia. Obtain complete history for the laboratory.
- General hospital admission guidelines are as follows:
- Patients with suspected or confirmed P falciparum or P knowlesi infection
- Children
- Pregnant women
- Immunodeficient individuals
- Intensive care unit admission guidelines are as follows:
- Immediate life-threatening complications present, such as coagulopathy or end-organ failure
- Presence of signs and symptoms consistent with cerebral malaria (eg, altered mental status, repeated seizures, coma)
- Patients who are nonimmune with a falciparum parasitemia greater than 2% or who are semi-immune with a P falciparum parasitemia greater than 5%
- Presence of any other severe malarial complications
- A reliable, semi-immune, adult patient with a P vivax, P ovale, or P malariae infection may be treated on an outpatient basis. However, special care must be taken if P malariae is diagnosed solely on the basis of a blood smear, as it may be confused with the sometimes fatal P knowlesi, an infection that would require inpatient treatment. Those treated as outpatients should have adequate follow-up care, including daily blood smears to confirm that the treatment is effective in decreasing parasitemia.
- If the infection is caused by an unidentified species or by mixed species, treat it as if it were caused by P falciparum. In the absence of known drug sensitivities, assume that the Plasmodium species in question is chloroquine resistant. If Southeast Asia is the origin of the infection, then assume mefloquine resistance.
- If a patient is diagnosed with P falciparum malaria with a parasitemia greater than 10% or if the patient is experiencing life-threatening complications (ie, coma, respiratory failure, coagulopathy, fulminant kidney failure), then investigate exchange transfusion as a treatment option. If transfusion is undertaken, it should continue until the parasitemia falls below 5%, although the mortality benefit of this intervention has not been proven.
- Administer parenteral quinidine, quinine, or artemisinin therapy in conjunction with exchange transfusion to eradicate the protozoa from the bloodstream.
- The World Health Organization also has guidelines on treatment of malaria.7
Consultations
It is recommended that the emergency physician contact an infectious disease clinician or the pathologist when confronted with a possible case of malaria based upon history and physical examination to ensure proper identification and diagnosis. It is particularly recommended that the physician contact the CDC directly for any known or suspected case. Consider HIV testing if indicated.
- To aid in identification of the species of Plasmodium, also notify the pathologist of the patient’s information, including the following:
- Determine where the patient has traveled and when the patient returned home.
- Determine if the patient has been diagnosed with malaria ever before. If so, find out which species of Plasmodium caused the previous infection.
- Determine what medication or prophylaxis the patient has taken, and find out when the last dose was administered.
- Determine if the patient has a history of blood transfusion or of nonsterile needle usage.
- Identify the date and time that the patient's blood sample was drawn and determine what condition the patient was in at that time (eg, patient was symptomatic, any periodicity of symptoms). Also provide an indication of the severity of illness.
- The Centers for Disease Control and Prevention has guidelines on the investigations of locally acquired mosquito-transmitted malaria.8
Medication
Antimalarial drugs have a rich history, since malaria was possibly the first human infection to be treated pharmacologically. The Chinese use of an extract from the sweet wormwood tree has led to artesemial drugs that, although expensive, are very effective. South American indigenous people have used the bark and root of the cinchona tree. The active ingredient in these medications turned out to be artemisinin and quinine, respectively, which now comprise 2 of the 4 major drug classes currently used to treat malaria. The 4 classes include quinoline-related compounds, antifolates, artemisinin derivatives, and antimicrobials.
No one drug that can eradicate all forms of the parasite's life cycle has been discovered or manufactured yet. Therefore, one or more classes of drugs often are given at the same time to combat malarial infection synergistically.
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.
Malaria treatment is not always straightforward. Contacting the CDC for the latest treatment guidelines and drug regimens is advised.9 Not all recommended treatment regimens or drugs are included below. Treatment in pregnancy and complicated malaria requires specialized drug regimens. Consult the CDC for further guidance. For the most recent CDC recommendations concerning malaria treatment, call the CDC Malaria Hotline at (770) 488-7788 (M-F, 8 am-4:30 pm, Eastern Time). For emergency consultation after hours, call (770) 488-7100 and request to speak with a CDC Malaria Branch clinician. The CDC table of guidelines for treatment of malaria in the United States can be downloaded as a pdf at Guidelines for Treatment of Malaria.
Treatment regimens are dependent on the geographic derivation of infection, the likely Plasmodium species, and the severity of disease presentation.
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 electrocardiograph 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 present. Those with normal QT intervals on ECG may not be at significant increased risk for drug-induced dysrhythmia, but caution is advised, particularly if the patient is taking multiple drug regimens, or if the patient is on other drugs affecting the QT interval.
Methemoglobinemia is a complication that may be associated with high-dose regimens of quinine the derivatives chloroquine and primaquine.10 A patient presenting with cyanosis and a normal PaO2 on room air should be suspected of having methemoglobinemia.
Malaria vaccine production and distribution continues to be in the research and development stage.
Antiprotozoal
Chloroquine phosphate remains the DOC if the patient is infected with a nonresistant strain of Plasmodium species. For chloroquine-resistant strains, a form of quinine is the drug next in line.
Chloroquine Phosphate (Aralen)
Inhibits parasite growth by concentrating within acid vesicles of the parasite and increasing its internal pH. In addition, inhibits hemoglobin utilization and metabolism by the parasite.
Adult
600 mg base (=1,000 mg salt) PO immediately, followed by
300 mg base (=500 mg salt) PO at 6, 24, and 48 h
Total dose: 1,500 mg base (=2,500 mg salt) 10 mg base/kg PO immediately, followed by 5 mg base/kg PO at 6-h, 24-h, and 48-h intervals
Species not identified
Pediatric
10 mg base/kg PO, not to exceed 600 mg; then 5 mg base/kg PO; not to exceed 300 mg at 6-h, 24-h, and 48-h intervals (total 25 mg base/kg)
Cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones
Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones; hypotension when given IV; impairs intradermal rabies vaccine
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Sodium channel blocking activity may increase toxicity of type Ia antidysrhythmic drugs or others with quinidinelike effects; ECG should be checked to monitor increased QRS interval effect
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur
Clindamycin (Cleocin)
Three major drug metabolites have been shown to have strong inhibitory effects, possibly by targeting apicoplast, a chloroplast-like organelle of uncertain function.
Inhibition causes modest antimalarial effects initially but is much more potent against progeny of treated parasites. Progeny inherits nonfunctional apicoplasts, blocking production of apicoplast proteins causing a "delayed-death effect".
Adult
20 mg base/kg/d PO divided tid for 7 d
Pediatric
Administer as in adults
Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile
Doxycycline (Vibramycin, Vibra-Tabs, Doryx)
May specifically impair progeny of apicoplast genes resulting in their abnormal cell division. Loss of apicoplast function in progeny treated parasites leads to slow but potent antimalarial effect.
Adult
100 mg PO bid for 7d
Pediatric
<8 years: Not recommended unless treatment benefit outweighs risks (consult CDC)
>8 years: 4 mg/kg/d PO divided bid for 7d
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Documented hypersensitivity; severe hepatic dysfunction
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Primaquine
If uncomplicated infection is caused by P vivax or P ovale, important to treat patient with primaquine to prevent relapse. If species is initially unknown, then identified as P vivax or P ovale, primaquine phosphate treatment should be initiated. Binds to DNA and may disrupt parasite's mitochondria, causing major disruption in metabolic process of the parasite. Exoerythrocytic forms of the parasite are inhibited.
Adult
30 mg base PO qd for 14 d
Pediatric
0.5 mg base/kg PO qd for 14 d or 0.8 mg base/kg PO once/wk for 14 d
Coadministration with quinacrine or other quinidinelike drugs may increase toxicity (see chloroquine)
Documented hypersensitivity; drugs that suppress bone marrow
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in G-6-PD deficiency and those with tendency to develop granulocytopenia
Quinine sulfate (Formula Q)
Used in chloroquine-resistant or unknown resistant infections. By increasing pH within intracellular organelles and possibly by intercalating into DNA of parasites, may inhibit growth of parasite.
Adult
542 mg base (=650 mg salt) PO tid for 3-7 d
Pediatric
8.3 mg base/kg (=10 mg salt/kg) PO tid for 3-7 d
Aluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates potential for toxicity; rifamycins decrease quinine concentrations by increasing hepatic clearance of quinine (effect can persist for several days after discontinuing rifamycins); concurrent administration of acetazolamide or sodium bicarbonate may increase toxicity by increasing quinine blood levels; quinine may enhance action of warfarin and other oral anticoagulants by decreasing synthesis of vitamin K-dependent clotting factors; digoxin serum concentrations may increase when digoxin administered concurrently with quinine; important to monitor digoxin levels periodically; quinidine may decrease plasma cholinesterase activity, causing decrease in metabolism of succinylcholine
Documented hypersensitivity; those with optic neuritis, tinnitus, G-6-PD deficiency, or history of blackwater fever
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and thus can cause cardiac dysrhythmias due to sodium channel blocking activity
Quinidine gluconate (Cardioquin, Quinalan, Quinidex, Quinora)
Indicated for severe or complicated malaria and used in conjunction with one of the following: doxycycline, tetracycline, or clindamycin. Increases pH within intracellular organelles and possibly by intercalating into DNA of parasites, may inhibit growth of parasite.
Adult
6.25 mg base/kg (=10 mg salt/kg) loading dose IV over 1-2 h, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion for at least 24 h
Length of treatment varies by geographic origin of infection (consult CDC)
Pediatric
Administer as in adults
Delays absorption of digoxin; antagonizes effects of antimyasthenics; mefloquine increases risk of seizures
Documented hypersensitivity; those with optic neuritis, tinnitus, G-6-PD deficiency, or history of cardiac dysrhythmias
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Caution in G-6-PD deficiency and in patients with a tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and can cause cardiac dysrhythmias via sodium channel blocking activity
Tetracycline (Achromycin V, Sumycin)
May specifically impair progeny of apicoplast genes resulting in their abnormal cell division. Loss of apicoplast function in progeny treated parasites leads to slow but potent antimalarial effect.
Adult
250 mg PO qid for 7 d
Pediatric
<8 years: Not recommended unless benefits outweigh risks (consult with CDC)
>8 years: 25 mg/kg/d PO divided qid for 7 d
Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Documented hypersensitivity; severe hepatic dysfunction
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines
Antimalarials
These agents inhibit growth of malarial pathogens by interfering with their stages of growth. US Food and Drug Administration has approved Coartem tablets (artemether and lumefantrine) for the treatment of acute, uncomplicated malaria infections.11Artemether 20 mg/lumefantrine 120 mg (Coartem)
Indicated for treatment of acute, uncomplicated Plasmodium falciparum malaria, the most dangerous form of malaria. Contains fixed ratio of 20 mg artemether and 120 mg lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartenisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta-hematin.
Adult
<35 kg body weight: Use pediatric dosing
>35 kg body weight: One dose is 4 tab; take 6 doses over 3-d period as described below
Day 1: Take 1 dose, followed 8 h later by 1 dose
Day 2: Take 1 dose bid
Day 3: Take 1 dose bid
Pediatric
<5 kg: Do not administer
5 to <15 kg: 1 tab
15 to <25 kg: 2 tab
25 to <35 kg: 3 tab
>35 kg: Administer as in adults
Take 6 doses over 3-d period as described for adults
CYP3A4 inhibitors (including antiretroviral drugs, macrolide antibiotics, antidepressants, and imidazole antifungal agents) or CYP2D6 inhibitors (eg, flecainide, tricyclic antidepressants) may increase toxicity of lumefantrine, increasing QT prolongation; halofantrine may increase toxicity of lumefantrine, increasing QT prolongation (not for concurrent administration; administer 1 mo apart); antimalarials quinine and quinidine may have additive effects on QT interval (use caution); not approved for severe or complicated P falciparum malaria; not approved for prevention of malaria
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
QT prolongation may occur; avoid use in patients with congenital prolongation of QT interval (family history) and known disturbances of electrolyte imbalance (including hypokalemia or hypomagnesemia); common adverse effects include headache, dizziness, loss of appetite, and fever
Mefloquine (Lariam)
Not used in complicated malaria. Acts as a blood schizonticide and may act by raising intravesicular pH within the parasite acid vesicles. Structurally similar to quinine.
Adult
15 mg base/kg PO, then 10 mg base/kg PO 6-8 h later (not to exceed 1250 mg; usually 750 mg PO, then 500 mg PO at 6-8 h)
684 mg base (=750 mg salt) PO as initial dose, followed by 456 mg base (=500 mg salt) PO given 6-12 h after initial dose
Total dose = 1,250 mg salt 13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed
by 9.1 mg base/kg (=10 mg salt/kg) PO given 6-12 h after initial dose
Pediatric
13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed by 9.1 mg base/kg (=10 mg salt/kg) PO given 6-12 h after initial dose
Mefloquine administered with beta-blockers, quinine, quinidine, antiarrhythmics, TCAs, or astemizole may cause ECG abnormalities or cardiac arrest; mefloquine and chloroquine administered concomitantly may increase risk of convulsions; concomitant administration with halofantrine may cause potentially fatal prolongation of QTc interval; valproic acid administered with mefloquine can increase risk of seizures by reducing valproic acid blood levels
Documented hypersensitivity; patients with seizure disorder, heart block, or psychiatric disorders
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use for >1 y not established; perform periodic evaluations, including LFTs, when using for prolonged periods; mefloquine may have cardiac depressant effects and antifibrillatory activity
Not recommended in infections originating in some Southeast Asian countries due to drug resistance
Artemether (Artenam)
Used only for severe or complicated malaria. Not FDA approved.
Adult
3.2 mg/kg IM (anterior thigh), then 1.6 mg/kg IM q24h until PO therapy is possible (never IV)
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Brainstem neurotoxicity and death in nonhuman primates have been reported; drug fever may occur
Artesunate
Experimental drug.
Adult
4 mg/kg PO qd for 3 d (total dose 12 mg/kg; 1 tab = 50 mg); for severe or complicated malaria, use 2.4 mg/kg IV load, then 1.2 mg/kg IV at 12 h and 24 h, then 1.2 mg/kg IV q24h until PO therapy is possible
Pediatric
Administer as in adults
Follow-up
Further Inpatient Care
- Perform thick and thin blood smears every 6-12 hours until parasitemia falls below 1% to ensure that the therapy instituted is clearing the infection.
- If parasitemia does not fall by 75% within 48 hours or if the blood is not cleared of parasites after 7 days, immediately initiate a different therapeutic regimen.
- Consult the CDC in all cases. Malaria infection may also be reportable to the local public health authority.
Further Outpatient Care
- Thick and thin blood smears should be obtained at least weekly for at least one month post treatment commencement to ensure clearance of parasitemia.
Deterrence/Prevention
- Avoid endemic regions.
- Take the proper prophylactic drugs at proper intervals if traveling to endemic regions.
- Use topical insect repellent (30-35% diethyltoluamide [DEET]), especially from dusk to dawn.
- Wear long-sleeved permethrin-coated clothing if not allergic to permethrin; spray under beds, chairs, tables, and along walls.
- Sleep under fine-nylon netting impregnated with permethrin.
- Avoid wearing perfumes and colognes.
- Seek out medical attention immediately upon contracting any tropical fever or flulike illness.
- Chemoprophylaxis is available in many different forms.
- The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug.
- Before traveling, people should consult their physician and consult the CDC's Malaria and Traveler's Web site to determine the most appropriate chemoprophylaxis.12 Travel Medicine clinics are also a useful source of information and advice.
Complications
- Most complications are caused by P falciparum, and they may include the following:
- Coma (cerebral malaria)
- Defined as coma, altered mental status, or multiple seizures with P falciparum in the blood, cerebral malaria is the most common cause of death in patients with malaria. If untreated, this complication is lethal.
- Even with treatment, 15% of children and 20% of adults who develop cerebral malaria die.
- The symptoms of cerebral malaria are similar to those of toxic encephalopathy.
- Seizures (secondary either to hypoglycemia or cerebral malaria)
- Renal failure: As many as 30% of nonimmune adults infected with P falciparum suffer acute renal failure.
- Hypoglycemia
- Hemoglobinuria (blackwater fever)
- Blackwater fever is the passage of dark urine, described as Madeira wine-colored.
- Hemolysis, hemoglobinemia, and the subsequent hemoglobinuria and hemozoinuria cause this condition.
- Noncardiogenic pulmonary edema: This affliction is most common in pregnant women and results in death in 80% of patients.
- Profound hypoglycemia: Hypoglycemia often occurs in young children and pregnant women. It often is difficult to diagnose because adrenergic signs are not always present and because stupor already may have occurred in the patient.
- Lactic acidosis: This occurs when the microvasculature becomes clogged with P falciparum. If the venous lactate level reaches 45 mg/dL, a poor prognosis is very likely.
- Hemolysis resulting in severe anemia and jaundice
- Bleeding (coagulopathy)
- Coma (cerebral malaria)
Prognosis
- Most patients with uncomplicated malaria exhibit marked improvement within 48 hours after the initiation of treatment and are fever free after 96 hours.
- P falciparum infection carries a poor prognosis with a high mortality rate if untreated. However, if diagnosed early and treated appropriately, the prognosis is excellent.
Patient Education
- For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Malaria.
Miscellaneous
Medicolegal Pitfalls
- The emergency physician should have a high index of suspicion if a history of fever is accompanied by suggestive symptoms in a patient with a history of travel to an endemic region.
- Failure to consider malaria in the differential of a febrile illness following such travel, even if seemingly temporally remote, can result in significant morbidity or mortality, especially in children and pregnant or immunocompromised patients.
- Mixed infections involving more than one 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 treatment for P falciparum to avoid potentially incompletely or inadequately treating this more dangerous species.
- Failure to recognize cases for which, due to their relatively high complication and fatality rate, inpatient treatment is highly recommended, particularly those caused by P falciparum and P knowlesi.
- Importantly, although rare, malaria infection should be considered in patients with no history of travel who have otherwise unexplained fever, anemia, CNS dysfunction, or sepsis.
- Individuals traveling to malarial regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications.
Special Concerns
- 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 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 both the mother and the fetus. Therefore, they should be used, since the benefits of these drugs much outweigh the risks associated with leaving the infection untreated.
- To obtain the latest CDC recommendations for malaria prophylaxis and treatment, call the CDC Malaria Hotline at (770) 488-7788 (M-F, 8 am-4:30 pm, Eastern Time). For emergency consultation after hours, call (770) 488-7100 and request to speak with a CDC Malaria Branch clinician.
- 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.
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