Clinical communication
Malaria: a rising incidence in the United States

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Abstract

Malaria is frequently a deadly disease, particularly in tropical countries of the world where this protozoan infection is endemic. While physicians in tropical countries are familiar with the presentation, those who do not practice in endemic regions of the world may neglect to add tropical diseases to their differential diagnosis of fever. Epidemiologic data from the CDC show the number of cases of malaria being diagnosed in the United States in the last decade has risen sharply. With international travel continuing to rise, there is strong reason to consider malaria as a source of fever.

Introduction

Malaria is a mosquito-borne, protozoan infection that primarily affects red blood cells. The symptoms that result resemble many more common illnesses. Fever, malaise, myalgias, headache, and vomiting are a few of the usual findings that fail to distinguish this disease from numerous others. Unfortunately, particularly with certain species of malaria, death may result. Other prominent sequelae may include thrombocytopenia, severe anemia, renal failure, jaundice, hepatosplenomegaly, convulsions, and coma.

The vast majority of the world’s new cases and deaths due to malaria occur in sub-Saharan Africa. The concentration of poverty, political instability, and constant migration of non-immune refugees into endemic malarial areas has done much to drive these numbers (1). In addition to these factors, sub-Saharan Africa and other areas of the world such as Southeast Asia and South America have seen emergence of resistance to formerly very effective medications by various species of Plasmodium.

The prompt diagnosis of malaria requires that it be included in the differential diagnosis of illness in a febrile person with recent history of travel to an endemic area. Clinicians should ask febrile patients for a travel history, particularly when evaluating fever in international visitors, refugees, migrant laborers, and international travelers (2). Patients should be asked if they were born overseas, if they have traveled outside of the United States in the last 3 years, or if they have experienced prolonged residence abroad.

Section snippets

Pathophysiology

The clinical features, epidemiology, and pharmacologic efficacy of malaria infection are intimately related to the complex lifecycle of the Plasmodium parasites.

Human infection begins when sporozoites in the salivary glands of a female Anopheles mosquito are inoculated into the human host as the insect feeds. These parasites rapidly infect human hepatocytes, entering liver cells within 30 min of entering the human body (3). There, each sporozoite divides and differentiates to form up to 30,000

Severe malaria

Most cases of malaria are classified as mild or uncomplicated. As the degree of parasitemia in patients with P. falciparum rises above 2%, the risk of uncomplicated becoming severe malaria grows. Severe malaria is characterized by the development of certain clinical findings. Malaria is considered severe if renal failure, noncardiogenic pulmonary edema, severe anemia, jaundice, hemoglobinuria, seizures, parasitemia of greater than 5%, coma, circulatory collapse, or hypoglycemia develops in the

Human resistance to malaria

A multitude of human phenotypes confer partial resistance to malaria. Sickle cell trait results in decreased intra-erythrocytic ATPase activity, reducing the surplus energy available to support parasite proliferation (3). In addition, parasitized erythrocytes in sickle trait patients assume the sickle shape and are more easily removed by the spleen. Merozoites of P. vivax invade erythrocytes by binding to a lectin on the Duffy antigen. Thus, patients who lack this antigen are resistant to vivax

Malaria in pregnancy

Pregnant women have an increased risk of malarial infection and have more malignant courses than non-pregnant women. This susceptibility is most marked during the first pregnancy and decreases with subsequent pregnancies. In one study in Malawi, the prevalence of parasitemia was 66% in primigravids, 29% in second pregnancies, and 20.9% in subsequent pregnancies (7).

Increased susceptibility in the pregnant patient may be because of increased sequestration of parasites in the placenta. In one

Diagnosis

Malaria is the most important parasitic disease worldwide. Millions of people visit the tropics every year, areas that are teeming with malaria. As a result, cases of imported malaria have risen dramatically over the years. In 1996, the United Kingdom had over 2500 cases diagnosed with 11 deaths (16). In 1998, there were 1021 cases with 19 deaths in Germany (17).

For the last 100 years, when the diagnosis of malaria has been entertained, confirmation has been made with the demonstration of

Thick and thin blood smear

All four Plasmodium species may be identified using thick and thin blood smears. Two drops of finger-prick blood are placed upon a glass side. The first drop is spread into a thin film with a fine-feathered edge by using a second slide held at a 45-degree angle. Spreading the first drop over a 1.0 cm squared area makes the thick film. The slide is then air-dried. Anhydrous methanol is used to fix the thin smear. The thick smear is not fixed at all. Both smears are then colored with 3% Giemsa

Newer methods of detection

Though microscopy of Giemsa-stained thick and thin films remains the standard to diagnose malaria in the United States, newer approaches continue to be developed worldwide.

Antigen detection assays in dipstick format

A rapid simple dipstick test that uses monoclonal antibody to detect P. falciparum histidine-rich protein 2 antigens (HRP-2) in hemolyzed blood has been developed, having sensitivity and specificity anywhere from 86–100% 29, 30. So far, this dipstick format is only able to detect P. falciparum. Manufacturers are developing methods to detect other species, in particular P. vivax (20). With parasitemias lower than 100 organisms/μL, drops in sensitivities to 11–40% have been reported 26, 29. There

Molecular methods

Polymerase Chain Reaction (PCR) was developed to detect several or all four species. Assay performance and extraction procedures are evolving.

PCR assays have been shown to be able to detect fewer parasites than thick blood smears. Several studies have shown that false negative thick blood smears have in actuality been true positives when tested with PCR assay 40, 41. PCR may also hold an advantage over microscopy with respect to species identification 41, 42. PCR may be useful in

Resistance

At one time, chloroquine was effective therapy for all four human species of malaria no matter the area of the world where the disease was contracted. Toward the end of the 1950s, reports from the field began to emerge about growing resistance to chloroquine by P. falciparum. The Thai-Cambodian region as well as Colombia, South America were the first to experience treatment failures with chloroquine (43). East Africa recorded its first case of chloroquine-resistant P. falciparum in a returning

Antimalarial drugs

In treating malaria, the clinician should have information with regards to drug resistance in the area the disease was contracted. The latest recommendations regarding treatment may come from an infectious disease specialist or the Centers for Disease Control (CDC). Physicians having questions regarding chemoprophylaxis or treatment of malaria may call the CDC Malaria Epidemiology Branch at (404) 639-2888. The operator should be instructed to page the individual on-call for the ‘malaria

Chloroquine

Chloroquine-resistant P. falciparum has been identified in all malarial areas of the world. In 1978, Colombia and Thailand were the only two countries in the whole world that had chloroquine-resistant P. falciparum. By 1996, 72 countries worldwide had P. falciparum that needed alternatives to this aminoquinolone derivative for cure. Most of the Middle East, Mauritius, Egypt, Haiti, Dominican Republic, Argentina, Mexico, and Central America north of the Panama Canal are the only areas of the

Sulfadoxine-pyrimethamine (fansidar)

Most areas of Southeast Asia, Brazil, and Colombia have high levels of P. falciparum resistance to Fansidar. Fansidar remains highly effective in most of sub-Saharan Africa. However, low levels of resistance have been documented in central and eastern Africa. Higher levels of resistance have been noted in Tanzania and Rwandan refugees in Zaire 59, 60. The emergence of fansidar resistance is of great concern in Africa since it is the last of the available and affordable antimalarial drugs.

Mefloquine (lariam)

Mefloquine is a derivative of quinine that is used both prophylactically and therapeutically in areas with multi-drug resistant malaria. In chloroquine-resistant P. falciparum infections outside of Thailand, Myanmar, and Cambodia, mefloquine is 90 to 95% curative. Mefloquine resistance is of significant concern in the Thai-Myanmar and Thai-Cambodia regions. Strains of P. falciparum in these regions of Southeast Asia are heavily resistant with cure rates of only about 50% 47, 62, 63, 64.

Halofantrine

Halofantrine is a phenanthrene-methanol compound that affects the malaria parasite at the erythrocytic stage. The drug (24 mg/kg) cures only about 65% of chloroquine-resistant P. falciparum in Africa and Thailand and should not be employed against mefloquine-resistant strains 52, 66. Cardiac conduction abnormalities have been seen with this antimalarial as well as death in those with prolonged QT syndromes (67). Halofantrine is not available in the United States.

Quinine

Quinine remains an effective therapy for malaria although it shows signs of declining activity against P. falciparum in the border regions of Thailand (68). Cure rates have dropped to about 60% when used alone in this area of the world. Quinine resistance has been reported rarely in other areas of the world 69, 70. A quinine-tetracycline combination cures nearly 100% of P. falciparum infections no matter the region of the world where the disease is contracted. For patients requiring parenteral

Primaquine

This drug has little effect on the erythrocytic forms of malaria. Primaquine has its greatest utility in eradicating the hyponozoites of P. ovale and P. vivax. These dormant liver forms are not killed by other antimalarials. Fifteen mg base per day for 14 days is required for a radical cure. A particular strain of P. vivax, Chesson strain, from Papua, New Guinea requires twice this dose. Reports of primaquine resistant or refractory strains have surfaced although inadequate dosing on a per

Tetracyclines

Tetracyclines were found to have antimalarial activity 30 years ago. Tetracycline and its derivatives depress the activity of dihydrorotate dehydrogenase of the pyrimidine pathway in P. falciparum, probably secondary to inhibition of enzyme protein synthesis (74). Daily doxycycline has been shown to be an effective causal chemoprophylactic in Kenya, Thailand, and Indonesia 75, 76, 77. Doxycycline is now one of the recommended chemoprophylactic regimens for military personnel and tourists

Clindamycin

The combination of quinine and clindamycin has been used in South America. This combination has been used effectively in adults and children with acute malaria in Africa 80, 81. These two drugs have been found to be very effective against multi-drug resistant P. falciparum (82). Clindamycin and quinine may be of value in children and pregnant women, two groups where tetracyclines are contraindicated.

Artemisinins

Thus far, resistance to this class has not occurred. Artesunate (10 mg/kg given over 3 days) with mefloquine (25 mg/kg) has been reported to be 98% effective in multi-drug resistant P. falciparum as compared to 31% efficacy with mefloquine alone (83). This drug currently is not available in the United States. This class of drug is the fastest acting of all antimalarial drugs and has not shown significant toxicity (84).

Malarone (atovaquone and proguanil)

In July 2000, Malarone was approved for use in the United States. Each tablet contains 250 mg of atovaquone/100 mg proguanil. This medication may be used to either prevent or treat acute malaria acquired in areas with chloroquine and mefloquine-resistant P. falciparum.

None of the antimalarial drugs kill the parasite at all stages of its life cycle. Quinine, quinidine, chloroquine, mefloquine, and artemisinin kill parasites during the red blood cell cycle. These are the most potent

Chemoprophylaxis

The failure to take antimalarials before, during, and after returning home can be fatal if an individual is traveling to a malarial area and is likely to be bitten by an anopheline mosquito. From 1959 to 1987, there were 68 fatalities in U.S. travelers who developed P. falciparum malaria. Of these patients, 77% had not had chemoprophylaxis. Thirteen percent had taken a regimen known to be ineffective for the region they were visiting. Six percent had only taken the prescribed medication

Malaria in the United States

In the early 1990s, the United States was averaging 1,200 to 1,400 cases of malaria per year (87). In 1997, the CDC had reports of 1544 cases of malaria with onset of symptoms among persons in the United States or one of its territories. This represented an increase in reported cases of 10.9% as compared to the previous year (84). Once confirmed by blood smears, cases of malaria are reported to local and state health departments by health care providers or laboratory personnel. Ultimately,

Malaria vaccine

Even if only 30% effective, it is estimated that the development of a malaria vaccine would be the most cost-effective means to control the disease (88). With millions of deaths per year worldwide, there is great urgency to find a preventive measure such as a vaccine (89). Considerable effort has gone into developing a vaccine during the last two decades. However, the complexity in designing a vaccine for P. falciparum is significant. Because of the various life cycles of the protozoan,

Summary

Each year there are roughly 300 to 500 million new cases of malaria in the world with approximately 2,000,000 deaths (96). Nearly 90% of these new cases and deaths occur in children under 5 years of age in sub-Saharan Africa (96). With increasing travel, more and more individuals who visit malarial areas of the tropics are bringing the disease back home with them. The United States has had increasing numbers of cases diagnosed within its borders in the last few years.

Emergency physicians

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