Case Presentation
A 34-year-old Indian man presented to the hospital emergency department complaining of high fevers, chills, and sweats. He had arrived from Bombay, India, 6 days earlier and denied any illness before his departure. Soon after his arrival in the United States, he began experiencing fevers as high as 104°F, occurring every 6 to 8 hours. The day before, he began to feel progressively weak, with malaise, muscle aches, and nausea. He said he had no headache, neurologic signs or symptoms, diarrhea, or genitourinary complaints. His medical and surgical histories were unremarkable, and he took no medications. He did not use tobacco or alcohol and denied any history of drug use.

He had worked in a chemical plant in India. His wife and son, who had arrived in the United States several weeks ago, were not ill.

Physical examination showed the patient was awake and alert but ill-appearing. Vital signs were: temperature, 101°F; pulse, 112 beats/min; blood pressure, 98/60 mm Hg; and respiratory rate, 20 breaths/min. His skin was warm but without any rashes or petechiae. He had no scleral icterus and no oral or pharyngeal lesions. The neck was supple, without meningismus or adenopathy. His heart was tachycardic without a murmur, and his lungs were clear. Abdominal examination revealed no guarding or rebound and no evidence of splenomegaly. No edema of the arms or legs and no joint swelling or tenderness were noted. The neurologic examination was nonfocal.

A complete blood cell count revealed a white blood cell (WBC) count of 1.3 x 10⁹/L, with 59% neutrophils, 29% lymphocytes, and 7% monocytes. Hemoglobin was 13.0 g/dL, and hematocrit was 37.4%. The platelet count was 4000/mm³. A chemistry panel was normal, except for a total bilirubin level of 1.7 mg/dL. The international normalized ratio was slightly elevated at 1.7. Erythrocyte sedimentation rate was 12 mm/hour. A chest radiograph was normal.

Blood and urine cultures were obtained, and the patient was admitted to the hospital. Empiric treatment was initiated with intravenous (IV) ceftriaxone sodium (Rocephin). He was also given 10 units of platelets. In the interim, a peripheral smear was performed because of the low WBC count and thrombocytopenia, and malarial parasites were noted. Plasmodium falciparum was subsequently confirmed by a thin blood smear. The parasite density was estimated to be 3%. An infectious diseases consultant recommended antimalarial therapy with oral atovaquone/proguanil HCl (Malarone) and doxycycline (eg, Adoxa, Doryx, Periostat).

An abdominal ultrasound showed nonspecific prominence of the portal triads and a spleen size of 12.4 cm—the upper limit of normal. On his first day of hospitalization, the patient continued to have fevers up to 104°F and developed chest discomfort and shortness of breath. A repeat chest x-ray showed vascular congestion, interstitial edema, and small, bilateral pleural effusions. The findings were believed to be consistent with noncardiogenic pulmonary edema. His oxygen saturation was 90% but improved to 98% with 3 L of oxygen by nasal canula.

On day 2, his hemoglobin went down to 10.8 g/dL, but the WBC count had improved to 3.2 x 10⁹/L, and the platelet count increased to 56,000/mm³. Although he continued to have temperature spikes to 104°F through the third day of hospitalization, his overall clinical and respiratory status improved.

A repeat malarial smear showed a parasite density of less than 1%. By hospital day 4, the patient had been without fever for 24 hours, his WBC count was 4.0 x 10⁹/L, hemoglobin was 11.1 g/dL, and the platelet count was 66,000/mm³. Oxygen saturation had improved to 97% on room air. He had completed the recommended 3-day course of atovaquone/proguanil, and his blood cultures remained negative. The patient was discharged with instructions to complete the 7-day course of doxycycline.

Discussion
Malaria is one of the most common causes of illness worldwide and is seen with increasing frequency in the United States because of a greater incidence of international travel. Worldwide, more than 275 million cases occur annually, resulting in more than 1 million deaths, mostly involving children younger than 5 years old.¹ According to the Centers for Disease Control and Prevention (CDC), about 1500 cases are reported each year in the United States, but this number is likely an underestimate of the actual incidence.² 

Malaria is caused by 1 of 4 species of the protozoan parasite Plasmodium: P falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium ovale. Clinical manifestations of the disease in humans varies widely and is affected by the parasite species, as well as by the immune status and age of the host.³ In its early stages, falciparum malaria is clinically indistinguishable from infection with the other species. However, with disease progression, P falciparum produces the most severe disease and the most life-threatening complications.

The infection is transmitted by the bite of the female Anopheles mosquito. The insect injects the parasite from its salivary glands into the human host. The sporozoites travel to the liver, where they divide to form schizonts and then merozoites. The merozoites then invade the red blood cells (RBCs). Within the erythrocytes, the merozoites differentiate into trophozoites, which divide to become blood schizonts, and then mature back into merozoites. The cycle is repeated in the peripheral circulation (Figure 1). It is the cycle of rupture and infection of erythrocytes that is responsible for the fever pattern seen with malaria. The incubation period for P falciparum is 9 to 14 days; thus, it is likely that this patient was infected about 1 week before he left India.

Signs and symptoms
The clinical presentation of patients with malaria is very nonspecific. One study showed that malaria is misdiagnosed at initial presentation in more than 60% of the cases in nonendemic areas.⁴ About 80% of the malaria-related deaths in the United States are due to inappropriate chemoprophylaxis, delayed diagnosis, or incorrect therapy.⁵ Obtaining a travel history is clearly helpful when making this diagnosis. However, malaria should be considered in almost any patient with fever of unknown origin.

Initially, malaria manifests with myalgias, headache, nausea, and weakness. Signs and symptoms progress to fever, chills, and sweats (Table 1). The systemic manifestations of malaria bear many similarities to diseases caused by bacteria, rickettsia, and viruses. Even if the patient has a suspicious travel history, the physician should also consider typhoid fever, leptospirosis, acute HIV infection, early meningococcal disease, and arbovirus infections, such as Dengue fever (Table 2).

Features of severe malaria include seizures, delirium, or coma. Such central nervous system (CNS) findings suggest cerebral malaria, which is more common in children than in adults.³ Respiratory distress, disseminated intravascular coagulation, and acute renal failure may also occur with severe malaria. In general, severity of symptoms depends on a patient’s immune status, including previous exposure to malaria. Rash, pharyngitis, and lymphadenopathy are not associated with malaria, and such findings should prompt the physician to consider an alternative diagnosis.

The pathophysiology of malaria has historically been thought to involve sequestered erythrocytes adhering to vascular endothelial cells, leading to altered blood flow and ischemia.¹ However, more recent data suggest that adenosine triphosphate deficiency occurs in malaria (as well as in other infectious diseases) from the inability of mitochondria to use available oxygen, because of the effects of inflammatory cytokines, such as tumor necrosis factor-a, on them. Some researchers believe that it is cytokines’ activity and their capacity to control pathways through which oxygen supply to mitochondria is restricted that makes P falciparum malaria primarily an inflammatory, cytokine-driven disease.⁶ 

Laboratory diagnosis
The diagnosis of malaria is typically made by examination of thick and thin smears of the patient’s blood. Thick blood smears prepared with Giemsa or Field’s stain are more sensitive in detecting the parasites, because the blood is more concentrated, allowing for a greater volume of blood to be examined. However, thick smears are more difficult to read. A thin smear, which is a monolayer of RBCs, allows for accurate speciation and quantification of the parasite that are needed to guide treatment. Parasite density, which has treatment and prognostic value, is estimated from the percentage of infected RBCs on the thin smear using the oil immersion objective. The trophozoites of P falciparum have a ring form (Figure 2), with double chromatin dots (“headphone configuration”).

A negative smear makes malaria unlikely; however, nonimmune individuals may be infected with very low parasitic densities. Ideally, blood smears should be performed every 12 to 24 hours for 3 days to confirm response to treatment.² 

Rapid tests that are based on Plasmodium lactate dehydrogenase and plasmodial antigens have reported sensitivities of 90% to 100% and specificities of 95% to 100%⁷; they can be used to differentiate between P falciparum and nonfalciparum infections. However, these tests are not approved for use in the United States. Serologic tests for plasmodial antibody are performed in research laboratories, but they only identify previous infection. Such testing may be useful to confirm malarial infection in someone who was diagnosed and treated while traveling internationally.³ Nucleic acid amplification (eg, polymerase chain reaction) testing is another option but has limited availability and clinical applications. It can, however, be used to confirm positive blood smears and to identify the malarial species.³

Many laboratory abnormalities are often seen in patients with malaria, including anemia, neutropenia, thrombocytopenia, and elevated hepatic transaminase levels. The reason for diminished platelet counts is not clear but is likely due to a combination of adherence of infected RBCs to platelets, marrow suppression, and disseminated intravascular coagulation.^1,8 

Thrombocytopenia alone is not associated with bleeding. Patients who have partial immunity to malaria from past exposure often present with anemia, hypoalbuminemia, and hematuria. Hyponatremia and hypoglycemia are associated with severe malaria, more frequently in children.³

Treatment
Malaria treatment should not be started until the diagnosis is confirmed. The CDC guidelines note that “presumptive treatment” of malaria should be reserved for unusual circumstances, such as when there is a strong clinical suspicion, severe symptoms, or a lack of available laboratory tests.² Specific treatment is based on the species identified, clinical status of the patient, and drug susceptibility. To reiterate, infection with P falciparum causes a more severe clinical course than the other 3 species. Patients may rapidly progress to death if untreated; thus, prompt initiation of therapy is critical.

Malaria is classified as either uncomplicated or severe disease. For patients with uncomplicated disease, oral agents are acceptable. However, when signs of severe disease are present—such as impaired consciousness, severe normocytic anemia, renal failure, acute respiratory distress syndrome, jaundice, seizures, or a parasite burden of more than 5%—parenteral therapy is recommended.² For patients with severe malaria, death may occur within the first 48 hours secondary to cerebral malaria or to acute respiratory distress syndrome, the latter of which can have a delayed presentation, sometimes appearing after parasites are cleared.⁹ 

For uncomplicated P falciparum infections acquired in areas with chloroquine-resistant strains, treatment options include quinine sulfate plus doxycycline, tetracycline HCl (Sumycin), or clindamycin (Cleocin). The other recommended therapy is atovaquone/proguanil, which was used in this patient. A third option noted by the CDC is mefloquine HCl (Lariam), but this drug carries a high incidence of CNS toxicity and should only be given when either of the other agents cannot be used.²

Patients with severe disease should initially receive IV quinidine gluconate plus oral or IV doxycycline, tetracycline, or clindamycin. At least 24 hours of continuous therapy with quinidine or 3 intermittent infusions are recommended. Because of the cardiac effects of quinidine, patients should be monitored in an intensive care unit. Once the parasite burden drops below 1% and patients can take oral therapy, they can be switched to an oral agent. Quinidine therapy should be given for 3 days if the infection was acquired in Africa or South America and for 7 days if the infection was acquired in Southeast Asia. One of the secondary agents (doxycycline, tetracycline, or clindamycin) should be given for 7 days. The CDC also provides specific treatment recommendations for pregnant women and children.

Exchange transfusions have been used to treat severe malaria since 1974.² This therapy is recommended for patients with a parasite density of 10% to 15% or with cerebral malaria. This process removes infected RBCs but can lead to febrile and allergic reactions, fluid overload, hypocalcemia, and alloantibody sensitization. Recent recommendations from the World Health Organization note that exchange transfusions are “controversial” and that evidence from clinical trials is contradictory.¹⁰ They state that some centers use exchange transfusions for patients with parasite burdens greater than 20%.⁹ A recent case report indicated that this approach was a successful treatment for severe malaria in a young child.⁸

Prognosis/clinical outcomes
The majority of patients who are appropriately treated for malaria will do well. Some who are repeatedly exposed to malaria can become “semi-immune,” but it is not possible to make an accurate judgment on a patient’s immune status based on ethnicity or country of residence.⁹ As more individuals travel to malaria-endemic areas, consultation with physicians for specific drug prophylaxis is expected. The Malaria Vaccine Initiative is aggressively pursuing a vaccine, but an effective vaccine is at least a decade away.¹ 

Conclusion
Other protective measures, such as the use of repellents (eg, diethyltoluamide) to help prevent mosquito bites, are recommended. All patients should be instructed to seek medical help if they develop fever during or after a trip to an endemic area. Current information regarding malaria risks, drug resistance, and specific prophylactic regimens is readily available from the CDC at www.cdc.gov/travel/regionalmalaria/index.htm .

References
1. Greenwood BM, Bojang K, Whitty CJ, et al. Malaria. Lancet. 2005; 365:1487-1498.

2. Centers for Disease Control and Prevention. Guidelines for the treatment of malaria in the United States. Available at www.cdc.gov/malaria/pdf/treatmenttable.pdf

3. Stauffer W, Fischer PR. Diagnosis and treatment of malaria in children. Clin Infect Dis. 2003;37:1340-1348.

4. Kain KC, Harrington MA, Tennyson S, et al. Imported malaria: prospective analysis of problems in diagnosis and management. Clin Infect Dis. 1998;27:142-149.

5. Stauffer WM, Kamat D. Special challenges in the prevention and treatment of malaria in children. Curr Infect Dis Rep. 2003;5: 43-52.

6. Clark IA, Budd AC, Alleva LM, et al. Human malarial disease: a consequence of inflammatory cytokine release. Malar J. 2006;5:85.

7. Hill DR, Ericsson CD, Pearson RD, et al, for the Infectious Diseases Society of America. The practice of travel medicine: guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006; 43:1499-1539.

8. Fraser IP, Cserti CM, Dzik WH. A 3-year-old girl with fever after a visit to Africa. N Engl J Med. 2006;355: 1715-1722.

9. Whitty CJ, Lalloo D, Ustianowski A. Malaria: an update on treatment of adults in non-endemic countries. BMJ. 2006;333:241-245.

10. Guidelines for the treatment of malaria. Geneva, Switzerland: World Health Organization, 2006. Document no WHO/HTM/ MAL/2006.1108. Available at www.who.int/malaria/docs/TreatmentGuidelines2006.pdf