Parasites

Background and Importance

More than 41% of the world’s population lives in malarial areas where plasmodia are endemic (e.g., parts of Africa, Asia, Oceania, Central America, and South America). The World Health Organization (WHO) has estimated that in 2013, malaria was responsible for 198 million clinical episodes and 500,000 deaths. Most of these deaths were the result of infection with Plasmodium falciparum . Immigrants and returning travelers presenting with malarial symptoms warrant particular consideration as acute falciparum malaria, if left untreated, carries a high mortality. Although it is classically associated with cyclical fevers, malaria presents various symptoms, including headache and diarrhea. Fever is common but not universal at initial presentation. When fever is present, it is often continuous early in the course of illness. Some studies in low endemicity areas have suggested that the presence of fever or headache has a sensitivity greater than 95%. In recent years there has been an increase in the diagnosis of falciparum malaria in travelers returning to the United States; the most common region from which these travelers return is West Africa. Patients who have had a longer duration of travel and neglected to take prophylactic medications or who failed to adhere to prescribed regimens are at the greatest risk.

Most people contract malaria after being bitten by an infected vector mosquito in an endemic region. Other mechanisms of transmission have been reported, including blood transfusions, injection drug use with contaminated syringes, maternal-fetal perinatal transmission, transmission from infected organs after transplantation (worsened by immunosuppression), and what has been described as “airport malaria.” This occurs when the infected mosquito is transported from the endemic region and released at the airport when the plane arrives, surviving long enough to transmit the parasite to a human host and then dying without establishing itself in its new location.

Pathophysiology

Malaria is caused by one of five species of the protozoan parasite Plasmodium : P. falciparum, P. vivax, P. ovale, P. malariae , and P. knowlesi . Of these species, P. falciparum poses the greatest risk of severe disease and death to the infected host. The female Anopheles mosquito is the arthropod vector that transmits malaria. The female ingests plasmodial gametocytes from ingesting a blood meal from an infected source. The gametocytes reproduce in the gut of the mosquito, transitioning to their sporozoite phase and migrating to the salivary glands in preparation for transmission. The plasmodia parasites enter the bloodstream of their next human host from the salivary glands of the female Anopheles mosquito during her blood meal. The sporozoites are trophic for human liver parenchymal cells; in hepatocytes, they undergo multiple replication rounds to form liver (extraerythrocytic) schizonts. The hepatocytes rupture, usually within 2 to 10 days after infection, releasing merozoites into the bloodstream. The merozoites invade red blood cells (RBCs), transforming into trophozoites and feeding on the hemoglobin in RBCs. Trophozoites mature into erythrocytic schizonts, which divide asexually into additional merozoites. Eventually, the erythrocyte undergoes lysis, releasing merozoites capable of infecting additional red blood cells. Although some merozoites are destroyed by the host’s immune system, many enter new erythrocytes. As this cycle repeats itself, there is amplification of the number of infected erythrocytes. After several repetitions of the erythrocytic cycle, the process changes, and male or female macrogametocytes develop instead of merozoites. These gametes ingested by the mosquito, subsequently complete the reproductive cycle by fusion, which is accomplished sexually within the gut of a new female Anopheles mosquito after she feeds on the infected human.

Infection with P. vivax or P. ovale can manifest a dormant stage in human hepatocytes; this stage is known as the hypnozoite. Hypnozoites are metabolically inactive and thus less susceptible to standard pharmacologic therapies. Hypnozoites can eventually release merozoites into the blood stream weeks to months or even years after initial infection, initiating relapse in the host unless specific treatment for the hypnozoite stage was anticipated by the clinician treating the patient. Recrudescent infection occurs when primary blood stages of any species of Plasmodium are immunologically or pharmacologically controlled without being fully eradicated and the liver phase persists, thus leading to latent multiplication at a higher rate. This may occur later due to immune suppression or overlying acute illness. P. malariae can sometimes cause an initial asymptomatic infection, and clinical symptoms develop years or decades later.

Initial parasite replication cycles are asynchronous, as multiple liver schizonts may rupture and release merozoites into the bloodstream. The host immune response to these parasites can lead to cytokine production with fever and rigors, malaise, headache, and myalgia, in addition to a variety of other symptoms. Over time, cycles of parasite reproduction become synchronized, with 24-hour ( P. knowlesi), 48-hour ( P. falciparum, P. vivax, P. ovale) , or 72-hour ( P. malariae) intervals of fever. Erythrocytes parasitized by P. falciparum express the parasitic protein PfEMP1, which binds to several host endothelial proteins, leading to cytoadhesion. RBC adherence to the endothelium leads to stasis of blood flow and microvascular occlusion, which can cause hypoperfusion of end organs. End-organ hypoperfusion in the brain can led to seizure, coma, and cerebral edema, which can be fatal. Hypoperfusion of other organs may lead to lactic acidosis or renal failure. Cytoadherence of parasitized RBCs may also result in low measured levels of parasitemia or even false-negative blood smears due to sequestration of infected erythrocytes in capillary beds.

Clinical Features

Patients presenting with a fever or acute illness who have returned from travel in a region endemic for malaria should be evaluated for the possibility of malaria. Other signs and symptoms including anemia, headache, nausea, chills, lethargy, abdominal pain, and upper respiratory complaints should also be considered as manifestations of malaria.

P. falciparum is the malarial species most morbid to humans; it infects a larger percentage of the host’s RBCs and is trophic for neural tissue leading to cerebral edema, seizures, encephalopathy, hypoglycemia (especially in children), metabolic acidosis, severe anemia, high-output cardiac failure, renal failure, pulmonary edema, disseminated intravascular coagulation, and death. In chronic malarial infection, increased cellularity from the host’s exuberant immune response may lead to hepatosplenomegaly. Within the liver, parasites and malarial pigment distend the Kupffer cells. Parasitized RBCs also adhere to the sinusoidal system of the spleen, reducing its immunologic effectiveness. Anemia results from acute and chronic hemolysis. Hemoglobinuria caused by severe hemolysis leading to renal failure, known as blackwater fever, may occur in patients with chronic or acute falciparum malaria.

Signs of severe malaria requiring immediate IV antimalarial treatment include prostration, altered mental status (Glasgow coma scale <11), more than two generalized seizures, severe anemia (hemoglobin < 7 g/dL), acute renal failure (creatinine > 3 mg/dL or blood urea > 20 mmol/L), hyperbilirubinemia or clinical jaundice (total bilirubin > 3 mg/dL), respiratory distress or pulmonary edema, shock, hypoglycemia (glucose < 40 mg/dL), spontaneous bleeding or DIC, acidosis (bicarbonate < 15 mmol/L or lactate > 5 mmol/L), hemoglobinuria, and greater than 2% parasitemia on blood smear (i.e., more than 2% of the patient’s RBCs contain malarial schizonts).

Cerebral malaria is a life-threatening complication of P. falciparum infection. Parasitized RBCs express malarial cell surface glycoproteins called knobs which adhere to capillary walls, resulting in sludging in the cerebral microvasculature. Impaired circulation leads to localized ischemia, capillary leakage, and petechial hemorrhages. Clinical manifestations of cerebral malaria include fever, altered mental status including obtundation and coma, and, not uncommonly, seizures. A careful history, rapid diagnosis, and immediate initiation of therapy are essential to prevent severe morbidity and death.

Differential Diagnosis

The emergency medicine clinician will most successfully diagnose parasitic infections by correlating historical features, such as exposure and travel history, with presenting symptoms that may be more nonspecific, including fever, anemia, peripheral edema, visual impairment, skin complaints, and symptoms related to the pulmonary, cardiovascular, and gastrointestinal (GI) systems. Other diagnostic considerations in at-risk travelers returning with febrile illness include more common conditions such as viral infections such as influenza or viral respiratory infections, and bacterial infections such as infectious diarrhea, urinary tract infections, and pneumonia. Cerebral malaria may manifest with confusion and mental status changes and should be differentiated from meningitis and encephalitis.

Malarial infection is often associated with anemia, particularly in children younger than 5 years. Anemia may develop quickly, from massive hemolysis in acute infection, or may have a more insidious onset, developing over months. Mature merozoites lyse parasitized RBCs. Uninfected RBCs undergo immune destruction from cell surface antibodies produced in response to parasite-associated changes in RBC surface proteins. This process of destruction is abetted by increased reticuloendothelial activity. The inhibition of erythropoietin secretion blunts the reticulocyte response in infected persons. Concomitant iron deficiency contributes to the severity of the anemia.

Diagnostic Testing

Microscopic examination of thick and thin blood films remains the gold standard for the diagnosis of malaria. Peripheral blood smears are stained with Giemsa or Wright stain and examined with ordinary light microscopy. The morphology of the intraerythrocytic schizonts allows the experienced clinician to determine the plasmodial species. In particular, P. falciparum has a very specific morphology, and the diagnosis can be made in a simply equipped laboratory. Even if the parasite is not visualized in the smear, treatment of malaria is indicated if the disease is suspected. The US Food and Drug Administration (FDA) has approved the use of an antigen-based rapid diagnostic test to screen patients. The Alere BinaxNOW kit provides qualitative testing for all four species and is available for approximately $5 per test. The test is not as sensitive as microscopy, which should still be performed for all patients with positive antigen test results to determine the species and severity of parasitemia.

Management

Untreated falciparum malaria can lead to coma and death; early treatment reduces morbidity and mortality. In the past, chloroquine phosphate was the treatment of choice for acute uncomplicated attacks of malaria. Resistance to chloroquine has been steadily increasing, and the drug is now recommended only in regions of known chloroquine sensitivity—Haiti, Dominican Republic, Central America north of the Panama Canal, and limited regions of the Middle East. For uncomplicated malarial infections in patients from chloroquine-resistant regions, oral quinine is given with doxycycline or clindamycin. Another suitable alternative combination is proguanil-atovaquone.

For severe P. falciparum infection or in patients unable to tolerate oral medication, intravenous (IV) artesunate is the recommended first-line treatment. It is available only as an expanded-access investigational new drug and must be obtained via request from the CDC (call CDC Malaria Hotline at 770-488-7788, Monday-Friday, 9 a.m. to 5 p.m. EST; at other hours call 770-488-7100). The artemisinin agents are excellent antimalarials and are available as enteral and parenteral preparations. They have a rapid onset of action and are well tolerated. An oral agent known as artemether-lumefantrine (Coartem) is now available for uncomplicated malaria, though other artemisinins are not approved for use in the United States.

Although not currently available in the United States, IV quinine or quinidine is another option for treatment of severe cases. Rapid infusion of IV quinine can cause profound hypoglycemia, as well as hyponatremia and coma vigil, a neurologic impairment due to high rates of parasite destruction. Patients should not receive IV quinine without cardiac monitoring.

Primaquine is used to eliminate the hepatic phases of P. ovale and P. vivax to prevent disease relapse. Primaquine therapy is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency because it can precipitate severe hemolysis.

Cerebral malaria is treated with IV quinine, quinidine, or artemisinin (as available), and supportive care, including mechanical ventilation for comatose patients and patients with noncardiogenic pulmonary edema, antiepileptics, and correction of acidosis and hypoglycemia. Hypoglycemia results from the high-grade falciparum parasitemia, as the protozoan is metabolically active, and the patient is often anorectic from the disease process or the quinine infusion and may be malnourished at baseline. The mortality rate is high, especially in children, but neurologic sequelae are rare if the patient recovers. Corticosteroids, including dexamethasone, provide no benefit and can worsen outcomes. A second antimalarial, such as doxycycline or clindamycin, should always be administered in conjunction with artemisinin or quinine in these cases.

Background and Importance

Babesiosis is a malaria-like illness that is becoming increasingly prevalent in the Northeastern United States ( Babesia microti ), northwestern United States ( Babesia gibsoni ), and Europe ( Babesia divergens ). Babesiosis is particularly endemic to Long Island, Cape Cod, Martha’s Vineyard, Nantucket, and Block Island. Babesiosis must be suspected, along with ehrlichiosis/anaplasmosis and Lyme disease, in patients who live or have traveled in these regions who present with flu-like illness (see Chapter 123 ). Babesia is a protozoan, similar in structure and life cycle to plasmodia. It is transmitted by the deer tick Ixodes dammini, which also is the vector of Lyme disease, ehrlichiosis, and anaplasmosis. Several cases of babesiosis have been correlated with transfusions with infected blood.

Clinical Features

Patients with babesiosis experience fatigue, anorexia, malaise, and emotional lability, with myalgia, chills, high spiking fevers, sweats, headache, and dark urine. Other manifestations include hepatosplenomegaly, anemia, thrombocytopenia, leukopenia, elevated liver enzyme levels (particularly the transaminases), and signs of hemolysis, with hyperbilirubinemia and decreased haptoglobin. In an otherwise healthy person, the disease may remit spontaneously. In asplenic, older, and immunocompromised patients, especially patients with AIDS and those taking corticosteroids, up to 85% of RBCs may contain organisms and infections may be fatal with vascular collapse and a septic shock-like presentation due to massive hemolysis, jaundice, renal failure, disseminated intravascular coagulation, hypotension, and adult respiratory distress syndrome (ARDS).

Diagnostic Testing

Diagnosis is based on clinical suspicion, multiple thin and thick blood smears ( Babesia organisms resemble plasmodia in blood smears), and serologic testing (convalescent titers may not be positive for several weeks after infection).

Management

The treatment of choice consists of atovaquone (750 mg BID orally) plus azithromycin (500–1000 mg once followed by 250 mg once daily orally) or, for severe illness, quinine (650 mg TID orally) plus clindamycin (1.2 g bid IV or 600 mg TID). Patients infected with B. divergens tend to be sicker and require more supportive care. Coinfection with Borrelia burgdorferi, the agent of Lyme disease, results in a more severe and prolonged illness.