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In a Shrinking World, Malaria Swells to Global Importance: Although we think of it as an exotic disease, malaria should be considered in every patient with a fever of unknown origin

Isaacs, Lawrence MD; Karras, David J. MD

doi: 10.1097/01.EEM.0000334180.89501.c9

As the world continues to shrink and individuals from all parts of the globe flood U.S. airports, emergency physicians need to be continually aware of the possibility of being faced with a case of malaria. While we tend to associate malaria with residents of (and travelers to) Africa, the disease is found on many other continents. There have even been cases of malaria in the U.S. not associated with recent travel to endemic locations, which is why malaria should be in the differential diagnosis of every patient with fever of unknown etiology.

Human malaria is caused by a bite of a female Anopheles mosquito infected with Plasmodium vivax, P. ovale, P. falciparum, or P. malariae. Malaria was a huge problem in the U.S. in the early 20th century, when approximately 500,000 cases were reported annually. In fact, the Centers for Disease Control and Prevention was founded as the Office of Malaria Control. Today the U.S. has almost eradicated domestic malaria, but there are still 300 to 500 million cases worldwide with more than two million annual deaths attributed to the disease.1

There also is the occasional case in the U.S. that cannot be traced to travel or blood transfusion, leaving open the possibility of domestically-acquired infection.2 The parasites can cross the placenta and lead to congenital malaria, and occasionally malaria is detected in the domestic blood supply.

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Malaria's Life Cycle

Malaria is found in half the world's countries, and is prominent in the equatorial areas of Africa, Asia, Central and South America, Oceania, and parts of the Caribbean. P. falciparum and P. vivax are the two most commonly identified types of malarial infections reported in the U.S. Most malaria cases coming from Africa are P. falciparum, and most of those are from West Africa. India, where the most common type is P. vivax, leads Asia in malaria cases. Honduras, Guatemala, and Haiti have the majority of the cases from Central America, with P. vivax responsible for the majority of cases from the former two and P. falciparum responsible for the vast majority of cases from Haiti.2

The life cycle of malaria is filled with terms that we all learned in school but with which we are no longer familiar. The mosquito injects sporozoites into the human host. These cells infect the host's liver, where they mature and are released as merozoites that invade red blood cells. The parasites further mature in the red cell, ultimately causing red cell lysis with release of even more organisms into the blood to infect more red cells. The cycle of maturation and red cell lysis occurs every 48 to 72 hours and are associated with the classic cyclical fevers.

In P. vivax and P. ovale infections, some sporozoites may remain dormant in hepatocytes for months and are responsible for relapsing infections. Finally, some of the cells emerging from the erythrocytes form reproductive cells that are ingested by other mosquitoes, where they reproduce, move to the salivary glands, and become ready to infect another human.

Fever is the most common presenting sign and symptom of malaria, but patients also may present with headache, nausea, vomiting, diarrhea, back pain, myalgias, or cough. The typical fever occurs every 48 hours with P. vivax and P. ovale infections and every 72 hours with P. malariae infections. While P. falciparum also cycles every 48 hours, continuous fevers with 48-hour spikes are more typically seen with this type of infection. The classic scenario is an onset of chills and rigors giving way to fevers as high a 104oF and ending with the fever breaking and the patient, diaphoretic and exhausted, falling asleep. The onset of symptoms usually occurs within one month of infection, but in a small number of cases, symptoms were reported as late as one year after exposure.

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Lab Abnormalities

Laboratory abnormalities are generally related to hemolysis, with low hematocrit and haptoglobin values and an elevated bilirubin. Hypoglycemia may be prominent, particularly with P. falciparum infections, and may be due to parasitic glucose uptake, host malnutrition and systemic responses to infection, or drug effects.3–5 Diagnosis is made by examining thick and thin blood smears for parasites. There is a commercially available ELISA for P. falciparium that may be as sensitive as the blood smear. 6,7

P. falciparum infection acts differently from other types in important ways. The continuous, rather than cyclical fever, was mentioned above. In addition, the parasite produces cytoadherence, in which the infected erythrocytes adhere to small blood vessels. P. falciparum infection may cause prominent CNS symptoms, including seizures and coma, pulmonary edema, renal failure, hypoglycemia, and severe anemia.8

Sickle-cell disease, either HbAS (trait) or HbSS, affords protection only from severe disease caused by P. falciparum. It is thought that the sickling, which occurs in the peripheral microvasculature, inhibits parasite growth both by deforming the red cell and by physically disrupting the parasite itself. This protects against the cerebral, renal, and pulmonary forms of the disease; it does not prevent infection from P. falciparum or the other three species of human malaria.4

The CDC publishes recommendations for travelers to malaria-endemic areas.9 Chloroquine should be taken once weekly beginning one week before departure and continuing four weeks after return. Travelers to areas where chloroquine-resistant P. falciparum is prevalent, such as Southeast Asia, the Amazon region, and sub-Saharan Africa, should instead take mefloquine for prophylaxis or daily doxycycline as an alternative. A new drug, a combination of atovaquone and proguanil (Malarone), is another alternative. Other drugs include pyrimethamine-sulfadoxine (Fansidar), primaquine and hydrochloroquine sulfate (Plaquenil). P. falciparum also has been found to be Fansidar-resistant in Southeast Asia, South America, and parts of eastern and southern Africa. The full list of current recommendations, dosages, contraindications, and adverse affects are available at

Chloroquine is the drug of choice for treatment of all types of malaria infections acquired in non-resistant regions. It can be taken by children and pregnant women. IV quinidine is the therapy of choice if parenteral treatment is necessary. In chloroquine-resistant areas, the regimen depends on the type of malaria acquired. For resistant P. falciparum, quinine plus doxycycline or Fansidar or mefloquine alone, are reasonable choices. For resistant P. vivax, oral mefloquine alone or quinine plus doxycycline or Fansidar are the drugs of choice.9 Besides general supportive care, exchange transfusions have been recommended as a treatment modality for critically ill patients with hyperparasitemia. While most patients with P. vivax, ovale, or malariae with good follow-up may be discharged, patients with P. falciparum who have no natural immunity (such as visitors to endemic areas) should be hospitalized until a response to therapy is noted.9

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Drug-Resistant Pneumococcal Bacteria Increasing

As the use of macrolides increases in the United States, drug-resistant strains of Streptococcus pneumoniae have become more common, according to an article in the Oct. 17 issue of the Journal of the American Medical Association.

Investigators in the Active Bacterial Core Surveillance/Emerging Infections Program Network at the Centers for Disease Control and Prevention in Atlanta examined resistance to macrolide antibiotics among S. pneumoniae bacteria.

The authors analyzed data on 15,481 isolates from bacterial cultures from invasive S. pneumoniae infection collected by the CDC's Active Bacterial Core surveillance system in eight states. They focused on trends in macrolide use and resistance from 1993 to 1999, and the factors associated with resistance.

From 1993 to 1999, macrolide use increased 13 percent; macrolide use increased 320 percent among children younger than five years. Macrolide resistance increased from 10.6 percent in 1995 to 20.4 percent in 1999, the authors noted. “Most resistant strains have MICs in the range in which treatment failures have been reported,” they wrote.

The authors examined data on two subtypes of the S pneumoniae bacteria, the M phenotype, associated with moderate MICs, and the MLS-B phentoype, associated with high MICs and resistance to the antibiotic clindamycin. M phenotype isolates increased from 7.4 percent to 16.5 percent, while the proportion with the MLS-B phenotype was stable (3–4%), they reported. In 1999, M phenotype strains were more often from children than persons 5 years or older (25.2% vs. 12.6%) and from whites than blacks (19.3% vs. 11.2%). The authors suggest that strategies are needed to control increasing macrolide resistance, especially among children.

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1. World Health Organization. World malaria situation in 1994. Wkly Epidemiol Rec 1997;72:269.
2. Malaria Surveillance — United States,1998. Morb Mort Wkly Rep Dec. 7, 2001.
3. Taylor TE, Molyneux ME, Wirima JJ, et al. Blood glucose levels in Malawian children before and after administration of glucose for severe falciparum malaria. N Engl J Med 1988;319:1040.
4. Mandell, GL, ed. Principles and Practice of Infectious Disease. 5th Edition. Philadelphia: Churchill Livingstone, 2000. p. 2821.
5. White NJ, Warrell DA, Chanthavanich P, et al. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med 1983;309:61.
6. Parra ME, Evans CB, Taylor DW. Identification of Plasmodium falciparum histidine-rich protein 2 in the plasma of humans with malaria. J Clin Microbiol 1991;29:1629.
7. Palmer CJ, Lindo JF, Klaskala WI, et al. Evaluation of the OptiMAL test for rapid diagnosis for Plasmodium vivax and Plasmodium falciparum malaria. J.Clin Microbiol 1998;36:203.
8. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 1987;330:662.
9. Centers for Disease Control. National Center for Infectious Disease-Electronic pages. Prescription Drugs for Preventing Malaria, accessed Feb. 2, 2002.
© 2002 Lippincott Williams & Wilkins, Inc.