Malaria in the United States: The Approach to Diagnosis and Treatment

Lubna Mirza, MD
Malaria is the most deadly vector-borne illness known worldwide. Of the 4 types of plasmodia causing malaria, Plasmodium falciparum is the parasite responsible for the most lethal form of the disease and is most often the culprit in the United States. Because of its relative rarity in this country, as well as its nonspecific symptoms, the diagnosis can be easily missed. Malaria should be considered in any patient presenting with fever, or with other flulike symptoms, who has a history of travel to an endemic area. Many diagnostic tests are now available, but microscopic demonstration of malaria parasites on Giemsa-stained thick-and-thin blood films remains the gold standard. Treatment must be individualized based on the infecting species, the clinical status of the patient, and the likelihood of drug resistance.
In 2700 BC, several characteristic symptoms of what we now know as malaria were described in the Nei Ching (The Canon of Medicine), an ancient Chinese medical text. In 1880, Charles Louis Alphonse Laveran, a French army surgeon stationed in Constantine, Algeria, first detected parasites in the blood of a patient suffering from malaria. For this discovery, Laveran was awarded the Nobel Prize for medicine in 1907.1

Epidemiology
Malaria is the most deadly vector-borne disease known. Each year, an estimated 350 million to 500 million new cases occur worldwide, and 1 million deaths are attributable to the disease,2 predominantly among children in tropical developing countries. These statistics are particularly troubling, given that the disease is both preventable and treatable.
In the United States, 1528 cases of malaria were reported to the Centers for Disease Control and Prevention (CDC) in 2005, including 7 fatalities.2 This represents a 15.4% increase from the 1324 cases reported in 2004. Only 2 of the infections reported in 2005 originated in the United States, both as a result of congenital transmission. Of the imported cases, two thirds were acquired in Africa.2
Four types of plasmodia cause malaria:
Plasmodium falciparum, the most deadly form, predominates in sub-Saharan Africa, Southeast Asia, Haiti, the Amazon basin of South America, and the Dominican Republic.
Plasmodium vivax is most prevalent in Central America (particularly Honduras), the Middle East, India, and Mexico.2
Plasmodium ovale occurs mainly in West Africa.
Plasmodium malariae has a patchy worldwide distribution.2,3
Among patients diagnosed in the United States, P falciparum is identified in about 50% of all cases and P vivax in 22%. The other 2 types, P malariae and P ovale, are rarely seen in the United States, and account for only about 3.5% and 2.5% of all malaria cases, respectively.2
The 2 regions with the greatest intensity of malaria transmission are Oceania and sub-Saharan Africa.4 As many as 30,000 international travelers contract malaria each year, although only about 10,000 cases are reported.5 This is why chemoprophylaxis is extremely important when visiting endemic regions, but data show that many travelers do not adhere to the recommended prophylactic regimens. As many as two thirds of those diagnosed with malaria in the United States in 2005 did not take any chemoprophylaxis, and at least 43% were not fully compliant.2

Pathophysiology
The Anopheles mosquito is the vector that passes plasmodia from its saliva into the human body while it is obtaining a blood meal. Less common routes of transmission of the infection are blood transfusions and maternal-fetal transmission. Plasmodia circulate in the blood before invading red blood cells (RBCs) and eating their contents. P vivax predominates in expressing the cyclic pattern of the illness. Untreated, P vivax infection usually lasts for 2 to 3 months, during which the frequency and intensity of paroxysmal fevers decrease. However, between 23% and 44% of patients infected with P vivax will relapse within a few weeks, or as long as 5 years later.6
Blood droplet on a human host skin from the malaria-spreading Anopheles gamiae mosquito.Photo courtesy of CDC/WHO
P ovale infections are usually less severe and often resolve without treatment. But both P vivax and P ovale parasites may remain dormant in the liver and reactivate weeks or months after the initial infection. Patients infected with P malariae tend to be asymptomatic for an extended period; however, recrudescence is common and is often associated with nephrotic syndrome, which is thought to be caused by deposition of antibody-antigen complex on the glomeruli.7
P falciparum is the most malignant form of malaria. Unlike P vivax, which only attacks the youngest RBCs (the reticulocytes), P falciparum affects all RBCs and is therefore associated with the highest level of parasitemia of the 4 plasmodium species. It causes microvascular pathology, obstructing blood flow via the cytoadherence and sequestration of RBCs within small vessels. The infected cells adhere to uninfected RBCs, forming rosettes that clog the microcirculation. Rosetting is mediated by an interaction between P falciparum RBC membrane protein (which is exposed on the infected RBC surface) and receptors on the surface of uninfected RBCs, which ultimately can lead to secondary organ dysfunction and severe complications by clogging the vasculature. Individuals with a promoter polymorphism of RBC have a deficiency of sticky proteins on the RBC surface, which can decrease RBC rosetting and help protect against P falciparum malaria.
Malarial parasites replicate inside RBCs, inducing RBC cytolysis and stimulating the release of toxic metabolic byproducts into the bloodstream. This is responsible for the flulike symptoms of malaria—such as chills, headache, myalgias, and malaise—that occur in a cyclic pattern. The parasite may also cause jaundice and anemia.
Malaria-causing plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment called hemozoin. The parasites derive their energy solely from the anaerobic glycolysis of glucose to lactic acid; they metabolize glucose 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs by altering the cell membrane and making it less deformable, suppressing hematopoiesis by tumor necrosis factor-a released from the lysed RBCs, and increasing the clearance of RBCs by the spleen, which leads to anemia. Malaria also causes thrombocytopenia by increasing splenic sequestration of platelets and decreasing platelet survival time. Hepatosplenomegaly can also occur over time.7

Differential Diagnosis
The differential diagnosis of malaria is protean and includes babesiosis, Q fever, viral hemorrhagic fever, dengue fever, encephalitis, endocarditis, gastroenteritis, giardiasis, heat exhaustion and heatstroke, hepatitis, hypothermia, leishmaniasis, meningitis, mononucleosis, otitis media, pelvic inflammatory disease, pharyngitis, bacterial pneumonia, mycoplasma pneumonia, viral pneumonia, salmonella infection, sinusitis, tetanus, toxic shock syndrome, toxoplasmosis, and yellow fever.
The physician should also consider African trypanosomiasis, amebiasis and amebic liver abscess, brucellosis, cholera, collagen vascular disease, enteric fever, epidemic or louse-borne typhus, food-borne illness or toxin, Hodgkin's disease, relapsing fever, poliomyelitis, schistosomiasis (acute Katayama fever), and seizure disorder.
Infection with P falciparum can result in cerebral malaria, pulmonary edema, renal failure, rapidly developing anemia, coma, and eventually death. Death can be prevented if appropriate treatment is sought and received.7

Diagnosis
The history Because malaria is still relatively uncommon in North America, misdiagnosis is common.8 Estimates suggest that the diagnosis is overlooked in about 59% of cases.9
As primary care physicians, how often do we see malaria in the United States? Not often. One of our grandfathers was in Texas in 1986, when he developed symptoms of a malarial infection he had acquired in Pakistan. He underwent an extensive workup for severe anemia and renal failure and was finally diagnosed with malaria after about 40 blood samples had been obtained.
The diagnosis is made by a thorough history, physical examination, and laboratory evaluation. Think about malaria in any patient with a history of travel to an endemic area who presents with any malarial symptoms. Malaria should also be considered in any person with fever of unknown origin, regardless of travel history. The patient should be asked about all travel within the past year, because the onset of symptoms can be delayed.2,3 Most patients live in or have recently traveled to an endemic region; however, a few cases are reported each year among patients with no such travel history. Keep in mind that patients may not provide an accurate history, or they may represent the rare case of locally acquired infection.3
Patients suspected of being infected with malaria should be urgently evaluated. Inquire about the patient's immune status, age, allergies, other medical conditions, and medications. The course of the patient's illness can help differentiate between plasmodium species (Table 1).
Signs and symptoms Patients usually remain asymptomatic for at least 1 week after the infecting mosquito bite. Illness onset is within 30 days of arrival in the United States for 94% of patients infected with P falciparum and for 73% of those infected with P malariae; in the rarer P vivax and P ovale infections, symptoms may not appear for 1 year or more.2
Symptoms and signs are usually nonspecific and can resemble those of many other febrile illnesses.3 The most common symptom is fever, which affects at least 75% of all patients.3 Other symptoms and signs are listed in Table 2.
The clinical findings of malaria are:
Anemia
Fever
Hepatomegaly
Hypotension
Jaundice
Splenomegaly
Tachycardia
Testing The diagnosis of malaria can be confirmed by light microscopy examination of Giemsa-stained thick-and- thin blood smears. Because of the cyclic nature of the parasitemia, smears should be taken every 6 to 12 hours for 48 hours before ruling out malaria; however, the first smear is positive in as many as 99% of cases.9 The thick smear is more sensitive, but the thin smear allows examination of the morphologic features of both the parasites (including their density) and the host RBCs, which is helpful for species identification. Perform a pregnancy test when applicable.
Other tests that can be useful in the diagnosis of malaria include fluorescent microscopy, polymerase chain reaction, and antigen detection and serologic assays.
The first rapid test for malaria authorized for use in the United States (Binax NOW Malaria Test) was approved by the US Food and Drug Administration (FDA) in June 2007. This test has a sensitivity of 88% when performed at the bedside, but it can be used only to diagnose P falciparum infection.10
Nonspecific laboratory tests include hemoglobin, hematocrit, lactate dehydrogenase, platelet count, liver function tests, blood urea nitrogen, and creatinine measurements (Table 3).11-13 Laboratory testing can also uncover evidence of disseminated intravascular coagulation (DIC). Remember that anemia can be absent in acute infection.

Treatment
An algorithm for the initial assessment and management of malaria in adults (Figure) is derived from the UK treatment guidelines.14 But despite the availability of established guidelines, US physicians make errors in drug treatment in as many as 25% of patients, likely related to their unfamiliarity with the disease and the complexity of the drug treatment regimens.14,15
Treatment should not be initiated until the diagnosis has been confirmed by laboratory investigations.8 Once the diagnosis is verified, appropriate antimalarial treatment must be initiated immediately. The CDC should be contacted to obtain guidance on current pharmacologic therapy (CDC Malaria Hotline: 770-488-7788). The 3 important factors to consider when choosing treatment are:
The infecting Plasmodium species
The clinical status of the patient
The drug susceptibility of the infecting parasite.
Knowledge of the infecting species permits individualized treatment. P falciparum can cause rapidly progressive disease, coma, or even death if not treated properly; the other 3 types usually do not cause severe illness. However, patients infected with P vivax or P ovale must be treated for the dormant hypnozoite forms in the liver, to prevent relapse.
Drug therapy Clinical status refers to whether the patient has uncomplicated or severe disease. Those with uncomplicated malaria can be effectively treated with oral antimalarial agents. Patients with altered mental status, coma, severe anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, shock, DIC, acidosis, jaundice, hemoglobinuria, generalized convulsions, or parasitemia of more than 5% should receive urgent, aggressive intravenous (IV) drug therapy.8
The drug susceptibility of the infecting parasites is determined by the geographic area where the infection was acquired. Genetic tests for drug resistance are available, but they are expensive and time-consuming. If you suspect the diagnosis of malaria but cannot confirm it, or if the diagnosis is definite but the species is unknown, start treatment immediately using agents that have activity against P falciparum. The clinical and parasitologic status of the patient can then be monitored to determine if the treatment should be changed.
If malaria is subsequently determined to be secondary to P vivax or P ovale, a 14-day course of primaquine phosphate should be added to the regimen to eradicate liver hypnozoites and prevent relapse.16 Failing to prescribe primaquine to eradicate the liver forms of P vivax is the most common error made by US physicians.15
Chloroquine therapy/resistance Chloroquine remains the drug of choice for all P malariae infections, as well as for all P ovale and P vivax infections, except for P vivax infections acquired in Papua, New Guinea or Indonesia—2 areas with a high prevalence of chloroquine-resistant P vivax.
For P falciparum infections acquired in areas without known chloroquine resistance, oral chloroquine phosphate (Aralen Phosphate) remains the drug of choice. For P falciparum infections acquired in areas known to have chloroquine-resistant strains, 3 options are available:
Quinine sulfate (Qualaquin) plus doxycycline (eg, Adoxa, Doryx, Vibramycin), tetracycline (Sumycin), or clindamycin (Cleocin); quinine treatment should continue for 7 days for infections acquired in Southeast Asia and for 3 days for infections acquired in Africa or South America
Atovaquone/proguanil HCl (Malarone)
Mefloquine HCl (Lariam), which is associated with a high rate of severe neuropsychiatric adverse reactions and is recommended only when 1 of the first 2 options cannot be used.
In P malariae infection, treatment should be changed to the chloroquine-resistant drug regimen (as for P falciparum) if the patient does not respond to chloroquine.
Treatment options for chloroquine-resistant P vivax infections are:
Quinine sulfate plus either doxycycline or tetracycline
Mefloquine.
Both options are equally recommended.
Emerging Treatments
The World Health Organization (WHO) now regards artemisinin derivatives as the treatment of choice for chloroquine-resistant P falciparum.17 These agents are often used in Southeast Asia and China but had not been approved for use in the United States. One exception is that, in June 2007, the FDA approved the use of the artemisinin-derivative IV artesunate as an investigational new drug with a treatment protocol for hospitalized patients with malaria who require IV therapy for any of the following reasons17:
Severe malarial disease
High levels of malaria parasites in the blood
Inability to take oral medications
Lack of timely access to IV quinidine
Quinidine intolerance or contraindications
Lack of response to quinidine.
Artemisinin derivatives should preferably be combined with other antimalarial agents (eg, quinidine, clindamycin, tetracycline) to decrease the risk of treatment failure, recrudescence, and gametocyte carriage. Artemisinin has been studied both as monotherapy (administered for 5 to 7 days) and in combination with other agents.18
The United Nations Millennium Project and World Health Assembly has called on countries where malaria is endemic to establish national policies that will help at least 80% of patients with malaria and reduce the burden of malaria by 50% by 2010, and by 75% by 2015.19 Malaria-endemic countries must take necessary measures to improve their healthcare systems to fight malaria. Efforts aimed at reducing the transmission of malaria include insecticide-treated mosquito nets and the use of insecticides for indoor residual spraying.20 Making antimalarial combination drugs available free to the public will help reduce associated morbidity and mortality. The WHO is supporting ongoing research to develop new drugs and diagnostic tests. A number of malaria vaccines are currently being studied in clinical trials.21

Conclusion
Malaria is increasingly being diagnosed in the United States, primarily as a result of an increase in international travel to endemic areas. The nonspecific features of the disease and the sometimes complex treatment regimens can complicate the diagnosis and treatment. Taking the history of travel within the past 12 months of a patient with fever of unknown origin, or other common malaria symptoms, can help weed through the extensive differential diagnoses. Physicians should become familiar with the guidelines for the prevention, diagnosis, and treatment of malaria. When a patient is planning a trip to a country where malaria is endemic, chemoprophylaxis should be recommended.

PRACTICE POINTS
Malaria presents with nonspecific symptoms and can be fatal if misdiagnosed or inappropriately treated.
Consider malaria in patients with flulike symptoms who have traveled to Africa, Asia, the Middle East, or Central/South America within the past 12 months.
The presence of malaria parasites on thick-and-thin blood smears with light microscopy confirms the diagnosis.
Chloroquine is often the treatment of choice for malaria acquired in areas without chloroquineresistant strains.

SELF-ASSESSMENT TEST
Which of the following statements about malaria is true?
It cannot be acquired in the United States
Most infections diagnosed in US patients are caused by P falciparum
Most patients diagnosed in the United States acquired their infection in South America
The number of cases reported to the CDC decreased between 2004 and 2005
Which of the following features is most characteristic of P falciparum malaria?
History of travel to India
Recrudescence
Severe illness
Onset of symptoms >30 days after arrival in the United States
Which of these statements about the diagnosis of malaria is not true?
Thrombocytopenia is a nonspecific finding
Polymerase chain reaction assay is more sensitive than light microscopy
Light microscopy is more specific than fluorescent microscopy
Thick smear is more sensitive than thin smear
Urgent, aggressive IV antimalarial therapy is indicated for patients with the following situations, except:
Jaundice
Pulmonary edema
Acidosis
Parasitemia of 3%
Of the following treatments, which would not be appropriate for a patient with a chloroquine-resistant strain of P falciparum?
Quinine sulfate and primaquine phosphate
Quinine sulfate and doxycycline
Atovaquone/proguanil
Mefloquine
(Answers at end of references list)

References
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Iqbal J, Siddique A, Jameel M, et al. Persistent histidine-rich protein 2, parasite lactate dehydrogenase, and panmalarial antigen reactivity after clearance of Plasmodium falciparum monoinfection. J Clin Microbiol. 2004;42:4237-4241.
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Kuehn BM. "Roadmap" aids malaria vaccine efforts. JAMA. 2007; 298:849-851.
Answers: 1. B; 2. C; 3. B; 4. D; 5. A.