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From the Centers for Disease Control and Prevention
January 11, 2006

Late Relapse of

JAMA. 2006;295(2):154-155. doi:10.1001/jama.295.2.154

MMWR. 2005;54:1231-1233

Approximately 1,300 cases of malaria are reported each year in the United States; nearly all of these cases occur in travelers, many of whom fail to receive or adhere to prescribed chemoprophylaxis or do not follow recommendations for prevention of mosquito bites. Malaria can persist if not treated or if treated incorrectly (e.g., with an ineffective drug or an incorrect dosage of an effective drug).1 Early treatment is required to avoid severe illness or death. Although malaria typically becomes clinically apparent within 1 month of infection, cases can occur years after the last presumed exposure. In November 2004, CDC received a report of a late relapse of malaria in a Nigerian man aged 23 years in Philadelphia, Pennsylvania. His malaria was determined to have been caused by Plasmodium ovale, one of the four species of Plasmodium parasite that are transmitted by mosquitoes and cause malaria. The patient had been treated for malaria in Nigeria on multiple occasions, most recently 6 years before onset of his illness in the United States. This report describes the Philadelphia case, which underscores the importance of taking a detailed travel and immigration history when evaluating unexplained fever and considering malaria in the differential diagnosis.

Case Report

The man sought care at a hospital emergency department after 10 days of nocturnal fevers, chills, and night sweats, occurring every 48-72 hours. He had a history of identical symptoms that had been treated empirically as presumed malaria, a common practice with patients with unexplained fever in malaria-endemic areas with limited diagnostic capabilities; no laboratory tests had been performed in Nigeria to confirm this diagnosis, the most recent of which was made 6 years earlier. The patient did not recall which medications he had received. The patient said he had no unexplained episodes of fever during the 4 years since immigrating to the United States and no recent travel to Nigeria or any other area where malaria is endemic; moreover, the patient said he had not traveled outside of the Philadelphia area since immigrating.

The patient was afebrile in the emergency department. Physical examination was normal; the liver and spleen were not palpable. Laboratory work was notable only for hemoglobin of 12.8 g/dL (normal range: 14-18 g/dL) and total bilirubin of 5.0 mg/dL (normal: <1.5 mg/dL), with direct bilirubin of 0.4 mg/dL (normal range: 0-0.3 mg/dL). A peripheral blood film revealed P. ovale (0.2% of red blood cells infected). These blood-film results subsequently were confirmed at CDC.

The patient was admitted to the hospital for less than 2 hours and then discharged with a treatment regimen of 7 days of quinine and doxycycline; he was not administered chloroquine, the treatment of choice for P. ovale infection, because none was available at the hospital pharmacy and the regimen prescribed was an appropriate immediate alternative. His symptoms resolved within 48 hours. Subsequently, a screen for glucose-6-phosphate dehydrogenase (G6PD) deficiency was negative (a requirement for primaquine), and a 14-day course of primaquine (30 mg daily) was administered. After 4 months, the patient reported no further symptoms.

Reported by:

J Rubinstein, MD, Thomas Jefferson Univ/Frankford Torresdale Campus; RA Fischer, MD, Albert Einstein Medical Center, Philadelphia, Pennsylvania. RD Newman, MD, ME Parise, MD, SP Johnston, MS, J Young, MS, Div of Parasitic Diseases, National Center for Infectious Diseases, CDC.

CDC Editorial Note:

Malaria is caused by any of the four species of Plasmodium (P. falciparum, P. vivax, P. ovale, or P. malariae) parasite transmitted by the bite of an infective female Anopheles mosquito. Nearly all malaria cases in the United States occur among persons who have traveled to areas with ongoing transmission. Infections also can be acquired locally through exposure to infected blood products, by congenital transmission, or by local mosquito-borne transmission. Treatment decisions take into account the infecting Plasmodium species, percentage of red blood cells infected, likely geographic origin of the infection, and clinical status of the patient.2 With P. ovale and P. vivax infections, certain parasites can remain dormant in the liver (i.e., hypnozoites) before infecting red blood cells and causing a relapse, even after appropriate treatment of a blood-stage infection. Fewer relapses occur with P. ovale malaria than with P. vivax.3

Malaria caused by P. ovale is the least common malaria reported in the United States, accounting for only 2.6% of cases in 2003.1 However, in Nigeria, malaria caused by P. ovale is second only to P. falciparum in frequency. In one clinical study of U.S. cases of P. ovale, relapses occurred 17-255 days after the primary attack.3 Other reports describe a relapse occurring 45 months after treatment of the primary attack of P. ovale,4 and transmission of P. ovale from a blood donor exposed 7 years before donation.5

The case described in this report highlights the importance of taking a complete travel and immigration history from persons with unexplained febrile illnesses. The history should include all foreign travel, immigration details, and any history of malaria, including whether or not the malaria was laboratory confirmed. Primaquine, the only available drug that kills hypnozoites, is used to clear the liver of P. ovale and P. vivax hypnozoites and thereby prevent malaria relapses. When primaquine is administered presumptively in conjunction with a blood-stage prophylactic agent to prevent a possible P. vivax or P. ovale relapse, this therapy is called terminal prophylaxis or presumptive antirelapse therapy (PART).6 Primaquine used in conjunction with an effective drug for killing blood-stage parasites (i.e., schizonts) in a patient with P. vivax or P. ovale malaria is called radical cure. PART and radical cure are the current strategies for preventing P. vivax and P. ovale relapses.6

CDC recommends a primaquine phosphate dose of 30 mg (base) by mouth daily for 14 days. Primaquine must not be used during pregnancy because it can cross the placenta and cause hemolysis in a G6PD-deficient fetus. Because of the risk for hemolysis from primaquine, patients must be screened for G6PD deficiency before starting treatment. For persons with G6PD deficiency, radical cure options should be reviewed with a specialist in infectious disease or tropical medicine. Primaquine is not recommended for PART in persons with G6PD deficiency.7

Health-care practitioners should consider malaria in their differential diagnoses of patients who have unexplained fever and (1) have a history of malaria, (2) have lived in a malaria-endemic country, or (3) have traveled to a malaria-endemic country. A malaria blood film should be performed and appropriate treatment administered. Current guidelines for the diagnosis and treatment of malaria are available at http://www.cdc.gov/malaria.

REFERENCES: 7 available