the diagnosis of Traveler's Fever

This case is an example of malaria caused by Plasmodium falciparum. In the context of the patient's recent travel to Nigeria and presentation with fever, malaria was strongly suspected. The patient's blood smear was notable for 15% parasitemia, most likely P falciparum (as evidenced by the circles within some of the red blood cells [RBCs] in the smear seen in Figure 2). The other laboratory findings, such as the thrombocytopenia and elevated bilirubin, correlated with the disease burden. The elevated creatinine value was also noted, as this finding is sometimes seen in more aggressive cases of the disease; however, this usually resolves with time.

Worldwide, there are about 300-500 million new cases of malaria annually. Malaria is the most deadly vector-borne illness in the world, causing 3.5-5 million deaths annually. On average, 40% of the 50 million people who travel from industrialized to developing countries each year report some illness associated with their travel. Approximately 1,200 cases of malaria are reported each year in the United States among travelers; therefore, it is important to consider malaria as a possible cause of fever in the returning traveler.

Malaria results from an infection caused by any of the following 4 protozoa of the genus Plasmodium: falciparum, vivax, ovale and malariae. Transmission of the parasite occurs via the bite of the Anopheles mosquito. Once the protozoa are injected into the bloodstream, they enter the hepatic cells and reproduce; eventually, the hepatic cells erupt and release more protozoa into the host's circulation. These parasites then remain in the bloodstream, periodically invading erythrocytes, causing hemolysis, and infecting new RBCs.

The incubation period tends to be 9-18 days for P falciparum, P vivax and P ovale, but P malariae has an incubation period of 18-40 days. The most common parasites seen in the US are P falciparum, which is often found in travelers returning from Sub-Saharan Africa, and P vivax, which is found in those returning from Asia, Eastern Europe, and Latin America. The clinical presentation also varies between these 2 parasites: P falciparum often causes symptoms within the first month following the travel period, and it can be fatal; of patients infected with P vivax, 50% have symptoms within 1 month after travel, and approximately 2% of patients may have symptoms 1 year after exposure. The majority of patients infected with either parasite are usually symptomatic within the first 3 months after they return to the US.

The clinical presentation of malaria can vary widely and depends on the species of Plasmodium involved. Common symptoms include fever, malaise, myalgias, and headache, which may be accompanied by cough, abdominal pain, or diarrhea. Since these symptoms are non-specific, malaria should be considered in all febrile travelers, regardless of their clinical presentation. In fact, approximately 78-100% of patients presenting with malaria are febrile when they are first examined. The classically described fever patterns are rarely observed; however, when these fevers do occur at 48- to 72-hour intervals, this finding is virtually pathognomonic for P vivax, P ovale, and P malariae infections. This cyclical pattern of symptoms coincides with the regular interval of erythrocyte hemolysis. On examination, splenomegaly is found in 24-48% of patients, and patients may complain of abdominal pain. Severe malaria, usually caused by P falciparum, causes several manifestations, including prostration, impaired consciousness or coma, respiratory distress caused by pulmonary edema and acute respiratory distress syndrome (ARDS), seizures, circulatory collapse, abnormal bleeding (including disseminated intravascular coagulopathy), splenic rupture, jaundice, severe anemia, acute renal failure, and acidosis. The level of parasitemia often exceeds 5%.

The diagnosis of malaria is made by examination of both thin and thick blood smears. These smears are used to quantify the level of parasitemia, which is used to guide treatment. If the first smear is negative, it should be repeated at 12- to 24-hour intervals for 48-72 hours. If the diagnosis is clinically suspected and a sufficient laboratory diagnosis is not possible, empirical treatment for P falciparum should be started because the disease can be fatal if left untreated. Other laboratory findings, such as normocytic anemia, thrombocytopenia, low WBC count, elevated lactate dehydrogenase, and elevated bilirubin, are nonspecific, but they may provide clues to the diagnosis.

The treatment options for malaria vary according to the region where the traveler was likely to have acquired the infection. This is based on the local prevalence and antimalarial drug susceptibility of particular Plasmodium species. Chloroquine is the treatment of choice for those patients infected with P vivax, P ovale, and P malariae. Patients infected with either P vivax or P ovale must also take primaquine, as these species may lie dormant within the liver and are not eradicated by chloroquine alone. Failure to treat P vivax and P ovale with both agents frequently leads to recrudescence of the disease. If P falciparum has been eliminated as the causative agent, patients may be treated in the ambulatory setting. If P falciparum is suspected, treatment should be initiated as soon as possible, as severe illness or death can occur in as little as 1-2 days after presentation. The CDC recommends hospitalization in order to ensure that patients are able to tolerate oral therapy and have an appropriate response to treatment. For those patients returning from areas where Plasmodium species have known chloroquine resistance, such as Southern Asia, Sub-Saharan Africa, and Oceania, there are 3 available treatment options: (1) oral quinine along with tetracycline, doxycycline, or clindamycin; (2) atovaquone-proguanil; or (3) mefloquine along with doxycycline. Depending on the severity of the disease and the region where the parasite was acquired, different lengths of treatment are recommended; these vary from 3 to 7 days of quinine therapy and 7 days of antibiotics. For those patients with severe malaria, an initial course of doxycycline with quinidine, an intravenous isomer of quinine, is recommended until the parasite burden is <1%, at which point oral therapy should be initiated. Unfortunately, quinine and quinidine have several side effects, and patients must be closely monitored for cardiac dysrhythmias caused by prolongation of the QTc, profound asymptomatic hypoglycemia, and respiratory distress.

In this case, the diagnosis of malaria resulting from P falciparum infection was promptly made based on the patient's travel history and the severity of his symptoms. He was admitted to the pediatric intensive care unit for close observation because of the potentially dangerous side effects of treatment. The patient received a bolus of intravenous quinidine and clindamycin. His parasitemia was <0.5% on the second day of treatment, and the patient was switched to oral quinine therapy and clindamycin. His platelet and creatinine levels improved on hospital day 5, and he was discharged to home on oral therapy for a total of 7 days.