AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Predominantly observed in the tropics, malaria is a potentially life-threatening disease, and patients may present with fever and a wide range of symptoms. Humans are infected with Plasmodium protozoa when bitten by an infective female Anopheles mosquito vector.

Four species can cause disease: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Timely diagnosis of the correct species is required because the particular species of P falciparum can be fatal and is often resistant to standard chloroquine treatment. Occasionally, patients may be infected with more than a single species. P falciparum and P vivax are responsible for the majority of new infections. Each species has a defined area of endemicity, although geographic overlap is common. Species can usually be distinguished by morphology on a blood smear.

Malaria in travelers typically manifests weeks after patients leave the endemic area. In some patients, the disease manifests months or years later. Because symptomatic delay is common, history of even a remote exposure to an endemic area should be elicited. Symptoms of malaria are nonspecific, and because timely diagnosis and treatment are required, malaria should be considered in all patients from the tropics who present with fever.

Pathophysiology

Patients typically acquire malaria in an endemic area following a mosquito bite. Cases of airport malaria and infection secondary to transfusion of infected blood are extremely rare. Risk of infection depends on intensity of malaria transmission and use of precautions such as bed nets, diethyltoluamide (DEET), and malaria prophylaxis.

After a mosquito takes a blood meal, the malarial sporozoites enter hepatocytes (liver phase) within minutes and then emerge into the bloodstream after a few weeks. These merozoites rapidly enter erythrocytes and develop into trophozoites then schizonts over a period of days inside erythrocytes during the erythrocytic phase of the life cycle. Rupture of infected erythrocytes containing the schizont results in fever and merozoite release. The merozoites enter new red cells, and the process is repeated, resulting in a logarithmic increase in parasite burden.

The outcome of infection depends on host immunity. Individuals with immunity can spontaneously clear the parasites. In those without immunity, the parasites continue to expand the infection, and, persons infected with P falciparum, death can occur. A small percentage of parasites become gametocytes, which undergo sexual reproduction when taken up by the mosquito. These can develop into infective sporozoites, which continue the transmission cycle after a blood meal in a new host.

The mechanisms that underlie immunity remain poorly defined. Additionally, patients who develop immunity who then leave the endemic area may lose protection. Travelers who return to an endemic area may request a test to demonstrate immunity; however, no reliable markers of immunity exist, and waning of immunity should be kept in mind when these patients are advised.

Each species has a specific incubation period. Reviews of travelers returning from endemic areas have reported that P falciparum infection typically develops within one month of exposure, thereby establishing the basis for continuing antimalarial prophylaxis for 4 weeks upon return from an endemic area. This should be emphasized to the patient to enhance posttravel compliance. Rarely, P falciparum can cause the initial infection up to a year later. P vivax and P ovale may emerge weeks to months after the initial infection. Additionally, P vivax and P ovale have a hypnozoite form during which the parasite can linger in the liver for months before emerging and inducing recurrence after the initial infection. In addition to treating the organism in infected blood, treating the hypnozoite form with a second agent is critical to prevent relapse from this latent liver stage.

Severe disease is typically seen with P falciparum infection. This species is more virulent because it may create high levels of parasitemia and sequestration that contribute to end-organ damage. Sequestration is a specific property of this species. As it develops through the 48-hour life cycle, it demonstrates adherence properties, which result in the sequestration of the parasite in small postcapillary vessels. For this reason, only early forms are observed in the peripheral blood, before the sequestration property develops; this is an important diagnostic clue that the patient is infected with P falciparum.

Sequestration of parasites may contribute to mental status changes and coma, observed exclusively in P falciparum. In addition, cytokines and a high burden of parasites contribute to end organ disease. End organ disease may develop rapidly with P falciparum, and it specifically involves the central nervous system (CNS), lungs, and kidneys. These severe manifestations may occur in the nonimmune traveler or young children who live in endemic areas.

Frequency

United States

Malaria was endemic, but it has been eradicated in the United States. All cases are imported from patients traveling from endemic areas. Occasionally, infections in individuals who have not traveled occur near airports. This is secondary to a local mosquito becoming infected through a blood meal from an infected traveler or a plane with an infected mosquito; this mosquito then takes a blood meal from a local nontraveling resident and transmits the infection.

Each year, 25-30 million people travel to the tropics, and approximately 10,000-30,000 US and European travelers acquire malaria.

International

Approximately 40% of the world's population live in endemic areas and are at risk for malaria. An estimated 300-500 million infections develop each year.

Mortality/Morbidity

Approximately 1-3 million deaths occur per year, typically in children in sub-Saharan Africa infected with P falciparum. Heightened mortality occurs in primigravida patients and nonimmune travelers.

Age

Heightened mortality occurs in young children aged 6 months to 3 years who live in endemic areas. Travelers without immunity have heightened mortality regardless of age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they have traveled to a tropical area anytime in their life may enhance recall.
• Patients typically become symptomatic a few weeks after infection, although the host's previous exposure or immunity to malaria affects the symptomatology and incubation period. In addition, each Plasmodium species has a typical incubation period.
• Notably, P vivax, particularly in temperate areas of India, may manifest symptoms as many as 6-12 months after the host leaves the endemic area. In addition, patients infected with P vivax or P ovale may relapse after longer periods because of the hypnozoite stage in the liver. The hypnozoite form develops after initial infection and can remain dormant for months to years before entering the blood stream and producing symptoms.
• P malariae does not have a hypnozoite stage, but patients may have a prolonged, asymptomatic, erythrocytic infection that becomes symptomatic years after leaving the endemic area.

Physical

• Severity of illness is affected by previous exposure to malaria and patient age. In addition, various genetic factors may enhance or limit disease. Protective factors include sickle cell disease, hemoglobinopathies, and polymorphisms in the host's TNF (tumor necrosis factor) gene. New host genetic polymorphisms that confer protection or susceptibility continue to be defined. These protective mutations may lessen the likelihood of infection or severity of disease; none is completely protective.
• The periodicity of fever associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale; 72 h for P malariae) is not apparent during initial infection because of multiple broods emerging in the blood stream. In addition, the periodicity is often not observed in P falciparum infections. Patients with long-standing synchronous infections are more likely to present with classic fever patterns. In general, the occurrence of periodicity of fever is not a reliable clue to the diagnosis of malaria.
• Symptoms of malarial infection are nonspecific and may manifest as a flulike illness with fever, headache, malaise, fatigue, and muscle aches. Some patients may present with diarrhea and other GI symptoms. Immune individuals may be completely asymptomatic or present with mild anemia. Nonimmune patients may quickly become very ill. Severe malaria is primarily secondary to P falciparum, although death from splenic rupture has been reported in patients with non–P falciparum malaria.
• Severe malaria manifests as follows:
• • Cerebral malaria: Coma may occur. Coma can usually be distinguished from a postictal state secondary to generalized seizure if the patient does not regain consciousness after 30 minutes. When evaluating patients with coma-complicated malaria, hypoglycemia, and CNS infections should be excluded.
  • Severe anemia: The anemia is multifactorial and is usually associated with P falciparum infection. In nonimmune patients, anemia may be secondary to erythrocyte infection and loss of infected RBCs. Also, uninfected RBCs are inappropriately cleared, and bone marrow suppression may be involved.
  • Renal failure: This is a rare complication of malarial infection. Infected erythrocytes adhere to the microvasculature in the renal cortex, which often results in oliguric renal failure. Renal failure is typically reversible, and supportive dialysis is often needed until kidney function recovers. In rare cases, chronic infection with P malariae results in nephrotic syndrome.
  • Respiratory symptoms: Patients may have metabolic acidosis and associated respiratory distress. In addition, pulmonary edema can occur. Signs of malarial hyperpneic syndrome include alar flaring, chest retraction (intercostals or subcostal) use of accessory muscles for respirations, or abnormally deep breathing.

Causes

Four species can cause disease: P falciparum (which is the most deadly), P vivax, P ovale, and P malariae. Distinguishing among the various species, especially P falciparum, is imperative to assure proper treatment and to improve prognosis. Occasionally, patients may be infected with more than a single species. P falciparum and P vivax are responsible for most new infections. Each species has a defined area of endemicity, although geographic overlap is common. Species can be distinguished by morphology on a blood smear. In addition, rapid diagnostic tests that distinguish the species are available (eg, OptiMal)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Human immunodeficiency virus (HIV) infection
Viral illness
Bacteremia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Diagnosis should be supported by the identification of the parasites on a thin or thick blood smear. The only rare exception is P falciparum, in which all the parasites during the life cycle can be sequestered out of the peripheral blood in late-stage forms. If no alternative diagnosis is found in an at-risk patient with possible cerebral malaria (ie, the lumbar puncture is unrevealing), initiate therapy for presumptive malaria and continue to obtain additional blood smears to confirm the diagnosis. This is not an occult infection.
• Thick smears
• • Three thick and thin smears 12-24 hours apart should be obtained. The highest yield of peripheral parasites occurs during or soon after a fever spike; however, smears should not be delayed while awaiting fever spikes.
  • Thick smears are 20 times more sensitive than thin smears, but speciation may be more difficult.
  • Obtain finger-prick blood and place a drop on a glass slide. Mix the blood with the end of a second slide until the blood clots. Dry thoroughly, then apply Giemsa stain buffered to a pH of 7.2. Leave the stain on the slide for 30 minutes. Screen at least 100 fields, each containing approximately 20 WBCs, before reporting a thick smear negative. In nonimmune patients, parasitemia may be very low and a longer evaluation of the slide should be considered.
• Thin smears
• • Thin smears are less sensitive than thick smears, but speciation is easier.
  • Prepare the smear by placing a small drip of finger-prick blood on one end of a slide and then steadily draw the blood across the slide using a second slide at a 45° angle. Fix the sample in methanol and stain with Giemsa stain.
  • Parasitemia can be determined by counting the number of parasites per 1000 RBCs. If parasitemia is low, use the number of parasites per 500 WBCs corrected by the total RBC and WBC counts in order to get the number of parasites per microliter of blood volume.
• Alternative diagnostic methods
• • Alternative diagnostic methods typically are used if the lab does not have sufficient expertise in detecting parasites in blood smears.
  • Alternatively, methods that stain the parasite using acridine orange have been developed. These include the Kawamoto technique, in which blood smears on a slide are stained with acridine orange and examined with either a fluorescent microscope or a light microscope adapted with an interference filter system. This results in the differential staining of nuclear DNA in green and cytoplasmic RNA in red, which permits recognition of parasites.
  • The quantitative buffy coat (QBC) is a similar technique that is as sensitive as thick smears. Because results cannot be used to speciate Plasmodium, a thin smear must be examined.
  • Monoclonal antibody to histidine-rich protein-2 appears to be very sensitive and specific.
  • A rapid dipstick test that detects lactate dehydrogenase (LDH) of the parasite (eg, OptiMal) can also distinguish P falciparum from the other species. This is particularly useful if laboratory expertise in differentiating the species is lacking. Similar to blood smears, these rapid tests may provide negative results in the case of very low parasitemia and should be repeated if results are initially negative and the diagnosis remains unknown.
• Blood tests
• • In general, blood cultures should be drawn in a febrile patient, and typhoid often is part of the differential diagnosis for a patient returning from the tropics. In addition, patients from tropical areas may have more than one infection; maintaining a high suspicion for additional infections should be considered if patients are not responding to antimalarials.
  • Hypoglycemia may occur in patients with malarial infection and should be ruled out in patients with mental status changes.
  • Assess hemoglobin (decreased in 25%, often profoundly in young children), platelet counts (thrombocytopenia in 50-68%), and liver function tests (results abnormal in 50%).
  • Importantly, fewer than 5% of malaria patients have an elevated WBC count. If leukocytosis is present, the examiner should entertain a broader differential diagnosis.
  • If the patient is to be treated with primaquine, a glucose-6-phosphate dehydrogenase (G-6-PD) level should be obtained because primaquine can result in severe hemolysis in these patients.
  • If the patient has cerebral malaria, obtain a blood glucose level to rule out hypoglycemia as a cause of mental status changes. Note that intravenous quinine can induce hypoglycemia; therefore, blood glucose should be monitored when using this agent.

Procedures

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

Histologic Findings

Histologic Variations Among Plasmodium Species

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Speciating the parasite is critical. Infection with P falciparum may be more severe than infection with other species. In addition, P falciparum is resistant to chloroquine treatment except in Haiti, the Dominican Republic, parts of Central America, and parts of the Middle East. In the United States, patients with P falciparum are often treated on an inpatient basis in order to observe for complications attributable to either the illness or its treatment.

Consultations

Consider consulting an infectious disease specialist for assistance with diagnosis, speciation, patient treatment, and disease management. The Centers for Disease Control and Prevention (CDC) is an excellent resource if no local resources are available. The CDC Malaria hotline is 770-488-7788; 770-488-7100 is the telephone number to speak with an on-call malaria specialist.

Diet

Continue intake as tolerated.

Activity

Continue activity as tolerated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Whether a traveler needs malaria prophylaxis is an important question. This decision should be based on the traveler's detailed itinerary and should determine whether travel to areas where malaria is endemic and possibly drug resistant is planned. Travel to an urban area may not require malaria prophylaxis, while travel to more remote or underdeveloped cities does. Determine the patient's accommodations and time of exposure. Travel during the transmission season, camping, and long-term trips are high-risk behaviors. Transmission typically does not occur at elevations higher than 2000 m.

Recommendations regarding prophylaxis should be made after reviewing guidelines published by the Centers for Disease Control and Prevention as they apply to the planned itinerary. An excellent reference for malaria prophylaxis can be found at the Centers for Disease Control and Prevention Web site.

P falciparum exhibits widespread resistance to chloroquine. Resistance is rare in P vivax, and infections from P ovale and P malariae remain chloroquine sensitive.

Artesunate is not available in the United States but may be used at 4 mg/kg/d PO for 3 days.

DEET may be used to prevent transmission of the parasite through mosquitoes. Apply 95% DEET, which lasts up to 10-12 h, or 35% DEET, which lasts 4-6 h. In children, use a concentration of DEET less than 35%; apply sparingly only on exposed skin, and remove when no longer exposed. Toxicity that manifests as encephalopathy and seizures has been reported in children exposed to higher concentrations of DEET.

P falciparum drug resistance is common in endemic areas such as Africa. Standard antimalarials such as chloroquine and antifolates (sulfadoxine-pyrimethamine) are ineffective in many areas. Because of this increasing prevalence of drug resistance and a high likelihood of resistance development to new agents, combination therapy is now becoming the standard of care for treatment of P falciparum infection worldwide. Artemisinins, a new class of antimalarial agent, are often part of these newly recommended regimens. They are not yet available in the United States; however, other combination drugs such as atovaquone and proguanil HCL (Malarone) or quinine in combination remain highly efficacious.

Drug Category: Antimalarials

Inhibit growth by concentrating within acid vesicles of parasite, which increases internal pH of organism. Also inhibit hemoglobin utilization and parasite metabolism.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients who are quite ill or those with P falciparum infection should be considered for inpatient treatment to ensure that medicines are tolerated.
• Obtain blood smears every day to demonstrate response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health or cause any symptoms.

Further Outpatient Care

• Patients with non–P falciparum malaria who are well can be treated as outpatients. Obtain blood smears every day to demonstrate response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health.
• Occasionally, morphologic features do not permit distinction between P falciparum and other Plasmodium species. In such cases, patients from a P falciparum–endemic area should be presumed to have P falciparum and treated accordingly.

Deterrence/Prevention

• Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and use of insect repellants may also prevent infection.
• Adult-dose 95% DEET lasts as long as 10-12 hours, and 35% DEET lasts 4-6 hours. For children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when no longer exposed.
• Consider using bed nets that are treated with permethrin.
• Consider chemoprophylaxis with antimalarials for patients traveling to endemic areas.

Patient Education

• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Parasites and Worms Center. Also, see eMedicine's patient education articles Malaria, Foreign Travel, and Insect Bites.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider diagnosis
• • Malaria is often overlooked because patients typically present with nonspecific symptoms.
  • Patients may present with localized findings. Patients with malaria can have gastrointestinal or pulmonary symptoms, as well as other types of symptoms. All patients who have been exposed to malaria and present with fever should have blood smears sent to a laboratory.
  • In addition, malaria can still develop in patients who were compliant with malaria prophylaxis.
  • Obtaining blood smears is a simple and inexpensive method to determine if patients are infected.
• Failure to treat hypnozoite stage of P vivax and P ovale with primaquine to prevent relapse
• Failure to prescribe appropriate prophylaxis for travelers

Special Concerns

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

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ashley EA, White NJ. Artemisinin-based combinations. Curr Opin Infect Dis. Dec 2005;18(6):531-6. [Medline].
• Baird JK, Hoffman SL. Prevention of malaria in travelers. Med Clin North Am. Jul 1999;83(4):923-44, vi. [Medline].
• Croft A. Extracts from "Clinical Evidence." Malaria: prevention in travelers. BMJ. Jul 15 2000;321(7254):154-60. [Medline].
• Eliades MJ, Shah S, Nguyen-Dinh P, et al. Malaria surveillance--United States, 2003. MMWR Surveill Summ. Jun 3 2005;54(2):25-40. [Medline].
• Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. Dec 2005;4(12):827-40. [Medline].
• Kain KC, Keystone JS. Malaria in travelers. Epidemiology, disease, and prevention. Infect Dis Clin North Am. Jun 1998;12(2):267-84. [Medline].
• Kain KC, Harrington MA, Tennyson S. Imported malaria: prospective analysis of problems in diagnosis and management. Clin Infect Dis. Jul 1998;27(1):142-9. [Medline].
• Marsh K, Forster D, Waruiru C, et al. Indicators of life-threatening malaria in African children. N Engl J Med. May 25 1995;332(21):1399-404. [Medline].
• Plowe CV. Antimalarial drug resistance in Africa: strategies for monitoring and deterrence. Curr Top Microbiol Immunol. 2005;295:55-79. [Medline].
• White NJ. Antimalarial drug resistance. J Clin Invest. Apr 2004;113(8):1084-92. [Medline].

Article Last Updated: Apr 7, 2006