Few diseases match malaria in historical and global mortality. Within the United States, though the vast majority of cases are in the armed forces, nearly all civilian cases of malaria enter the health care system through the emergency department. Here, the risk of malaria is highest in returning travelers from endemic regions, especially those who failed to take chemopro-phylaxis, and who present with fever and systemic symptoms. Notably, the diagnosis is missed in 40% of United States fatal cases.¹

Given that delay to diagnosis and initiation of treatment may lead to death, emergency physicians should be able rapidly to diagnose malaria and initiate appropriate therapy.

Pathophysiology and Epidemiology

Malaria is caused by approximately 10 species of the Plasmodium protozoa. The five most common are P. falciparum, P. vivax, P. knowlesi, P. ovale, and P. malariae. The parasite is transmitted through the bite of the Anopheles female mosquito, with P. falciparum responsible for nearly all mortality. The patient is initially asymptomatic for

1-2 weeks while the parasite reproduces in the liver. Subsequently, the parasite is released into the bloodstream, where it reproduces within red blood cells until the cells hemolyze. The patient appears jaundiced and develops cyclical fever and systemic complaints. These often begin once the returning traveler has been home already for several days or weeks, but may be delayed for months to years.

The life cycle of the parasite forms the basis of treatment, as both liver and blood stages of the parasite must be eradicated. Dormant liver forms of P. vivax and P. ovale lead to relapse months to years later, despite prophylaxis and treatment.

Evaluation and Diagnosis

Returning travelers with fever should be questioned regarding travel to endemic regions, use of malaria prophylaxis medications, and the onset and periodicity of fevers. A thorough review of systems should be obtained.

As travel to endemic regions grows, the risk of malaria in the American traveler increases as well. Worldwide, an estimated 250 million cases and 1 million deaths were reported in 2008 alone. The United States has approximately 1,500 cases and 15 deaths every year. A few “hot spots” account for most cases. Travel to Nigeria, India, Ghana, Uganda, Afghanistan, and Honduras accounts for 60% of cases. Fifty percent of cases present to the urban emergency departments of New York, California, Texas, Georgia, and Illinois.²

Although just 20% of travelers take appropriate prophylaxis, it is important to inquire about the specific medication taken. Not all prophylaxis is created equal. Dormant liver forms of P. vivax and P. ovale may lead to relapse months to years after travel if mefloquine, doxycycline, or atovaquone-proguanil (Malarone) is not used. The area of travel should also be investigated for chloroquine-resistance via the Centers for Disease Control and Prevention’s Malaria Web site.

Lastly, adherence to the regimen for prophylaxis should be assessed as intermittent dosing can mask subclinical parasitemia.

The symptoms of malaria mimic a viral syndrome or gastroenteritis. More than 75% of cases will present with fever, chills/rigors, and headache. In 50% of cases, symptoms will include fatigue, anorexia, arthralgia, or nausea/emesis.³ Occasionally, patients will report a periodic fever with spikes occurring every 48 to 72 hours—a classic but unreliable sign of malaria.

Physical exam findings that are consistent with uncomplicated malaria include hepatosplenomegaly (indicating hemolysis and sequestration), mild abdominal tenderness, and evidence of mild dehydration.

Severe malaria (see sidebar) indicates heightened parasitemia and is a true medical emergency. The presence of coma indicates cerebral malaria, which is uniformly and rapidly fatal if untreated. Special attention should be given to pregnant women with malaria, as they are relatively immunocompromised and decompensate quickly.⁵

ED Work-Up and Management

The clinician evaluating fever in the recent traveler must remember the seven deadly infections that can kill within hours of presentation if not treated urgently and appropriately. These are summarized by the mnemonic HERE I AM: Hantavirus, Ebola, Rabies, Enteritis, Influenza, Arboviruses (e.g., Dengue and West Nile), and Malaria.

All cases of suspected malaria are treated as chloroquine-resistant P. falciparum until proven otherwise. Therefore, the region of travel and malaria species are not initially important. Emergency department therapy is based on stratifying uncomplicated versus severe malaria. Early infectious disease consultation is recommended.

If the clinical picture is consistent with malaria, rapidly obtain a CBC, BMP, thick and thin smears, blood parasite levels, and a type and screen. Blood for smears should be collected in red-top Vacutainer tubes, as lavender-top EDTA or blue-top heparinized tubes preferentially lyse infected RBCs. Many large hospitals employ rapid antigen detection. However, if there is a delay in diagnosis longer than 3 hours and clinical suspicion remains high, empiric therapy with an antimalarial is indicated.

Thin smears are easily prepared and are diagnostic in 95% of cases. The emergency physician should call the pathology department to express the concern for malaria. The presence of intracellular ringed forms (see image) confirms the diagnosis.

However, a single negative smear does not rule out malaria. The CDC recommends obtaining smears every 12-24 hours for 3 consecutive days to rule out malaria.^5,6

Resuscitation should occur with isotonic fluids supplemented with glucose-containing crystalloid (D5NS or D5LR) to maintain euvolemia and euglycemia. Early seizure prophylaxis with benzodiazepines or other anti-epileptics should be considered in cases of suspected severe malaria. In addition, parasitemia above 2% (5% in those who may be partially immune) or signs of severe malaria should mobilize early resources for exchange transfusion and ICU admission.^4,5,7

Antimalarial Drug Treatment Options

Uncomplicated malaria is treated with a course of oral medication. A common regimen consists of four tabs of atovaquone-proguanil 250/100 (Malarone) once daily for

3 days, but antiparasitic regimens are best chosen according to infectious disease consultation. While mild cases of malaria with species other than P. falciparum or P. knowlesi may be safe to discharge home, most physicians would likely admit the patient to assure proper treatment and follow-up.

If the patient cannot tolerate oral medication or severe malaria is suspected, treatment with parenteral medication is indicated. Quinidine gluconate 10 mg/kg IV over 1 hour may be used, followed by infusion at 0.02 mg/kg per minute AND doxycycline 100 mg IV every 12 hours. Quinidine administration requires cardiac monitoring and very frequent (hourly) EKGs to monitor the QT interval, given the risk of torsades des pointes. Because of cardiotoxicity, treatment is recommended in consultation with cardiology in an ICU setting.

Given the cardiotoxicity of quinidine, artesunate has been approved for parenteral treatment of malaria. Artesunate has several benefits over quinidine, and it is the mainstay of treatment of malaria outside the United States. Artesunate does not require cardiac monitoring, and the drug is easily dosed every 12 hours.⁸ It is available from the CDC Malaria Branch hotline (770-488-7100) at no charge, and is stored at 20 quarantined sites across the continental United States.

Summary

Fever in a traveler presenting to the emergency department should prompt an evaluation for malaria. History should focus on use of chemoprophylaxis, travel to endemic regions, and onset and type of symptoms. Diagnosis is confirmed by peripheral blood smear, and therapy is initiated in the emergency department based on risk stratification into uncomplicated or severe malaria.

Emergency physicians should be aware of possible pitfalls in the diagnosis, as well as signs of severe malaria. In cases where oral medications are not tolerated or quinidine is contraindicated, IV artesunate is readily available from the CDC.

References

1. Greenwood BM, K Bojang, CJ Whitty, and GA Targett. Malaria. Lancet. 2005 April 23-29; 365(9469):1487-98.
2. Centers for Disease Control and Prevention. The Impact of Malaria, a Leading Cause of Death Worldwide. (www.cdc.gov/malaria/impact/index.htm).
3. Stanley J. Malaria. Emergency Medicine Clinics of North America. 1997 February; 15(1):113-55.
4. World Health Organization. Guidelines for the Treatment of Malaria. 2006.
5. Centers for Disease Control and Prevention. Treatment of Malaria: Guidelines for Clinicians. (Last updated May 18, 2009).
6. Bailey JW, Williams J, Bain BJ, Parker-Williams J, Chiodini P. General Haematology Task Force. Guideline for laboratory diagnosis of malaria. London (UK): British Committee for Standards in Haematology. 2007;19.
7. Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: a systematic review. JAMA. May 23 2007;297(20):2264-77.
8. Rosenthal PJ. Artesunate for the treatment of severe malaria. New England Journal of Medicine. 2008 April 24; 358(17):1829-36.
9. Centers for Disease Control and Prevention. Malaria. Topic Home. Last updated May 21, 2009. Available at www.cdc.gov/malaria/index.htm.
10. “Intracellular ringed forms, malaria.” Charles E. Hess, M.D. and Lindsey Krstic, B.A.

Contributors

Dr. Malya is a second-year emergency medicine resident at the University of Chicago. Dr. Pillow is an assistant professor at Baylor College of Medicine and assistant director of medical education at the Ben Taub Emergency Center in Houston, Texas. Medical Editor Dr. Robert C. Solomon is an attending emergency physician at Trinity Health System in Steubenville, Ohio, and clinical assistant professor of emergency medicine at the West Virginia School of Osteopathic Medicine.

Disclosures

In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter. Dr. Malya, Dr. Pillow, and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this educational activity. “Focus on: Malaria” has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). ACEP is accredited by the ACCME to provide continuing medical education for physicians. ACEP designates this educational activity for a maximum of one Category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he or she actually spent in the educational activity. “Focus On: Malaria” is approved by ACEP for one ACEP Category 1 credit.

Disclaimer

ACEP makes every effort to ensure that contributors to College-sponsored programs are knowledgeable authorities in their fields. Participants are nevertheless advised that the statements and opinions expressed in this article are provided as guidelines and should not be construed as College policy. The material contained herein is not intended to establish policy, procedure, or a standard of care. The views expressed in this article are those of the contributors and not necessarily the opinion or recommendation of ACEP. The College disclaims any liability or responsibility for the consequences of any actions taken in reliance on those statements or opinions.