Babesiosis

Background

Babesiosis is a tick-borne malaria-like illness caused by species of the intraerythrocytic protozoan Babesia. Humans are opportunistic hosts for Babesia when bitten by nymph or adult ticks. Currently, Babesia infection is transmitted by various tick vectors in Europe, Asia, and the northwestern and northeastern United States.

Human babesiosis is a zoonotic infection in which ticks transmit Babesia organisms from a vertebrate reservoir to humans^{[1, 2]} ; the infection is incidental in humans. The primary Babesia species that infect cattle include Babesia divergens, Babesia bigemina, Babesia bovis, and Babesia major. In horses, the main species is Babesia equi. Babesia canis is the primary species in dogs, and Babesia felis is the main species in cats. Babesia microti is the species found in mice.

Babesia species and organisms of the closely related genus Theileria have worldwide distribution, parasitizing the erythrocytes of wild and domestic animals. These parasites are commonly called piroplasms because of the pear-shaped forms found within infected red blood cells (RBCs). Most human babesial infections are caused by B microti (found only in the United States) or by B divergens and B bovis (found only in Europe).

Human babesiosis is infrequent and occurs in limited geographic locations. In the United States, it is usually an asymptomatic infection in healthy individuals. Several groups of patients become symptomatic, and, within these subpopulations, significant morbidity and mortality occur. The disease most severely affects patients who are elderly, immunocompromised, or asplenic.

Babesiosis is difficult to diagnose. Although the index of suspicion should be high in areas endemic for Babesia infection, patients with babesiosis have few, if any, localizing signs to suggest the disease. Confirmation of the diagnosis depends on the degree of parasitemia and the expertise and experience of the laboratory personnel.

Most patients infected by B microti who are otherwise healthy appear to have a mild illness and typically recover without specific chemotherapy; however, treatment is recommended for all diagnosed cases to prevent sequelae and potential transmission through blood donation. In addition, patients should be advised to take precautions against tick exposure and to refrain from donating blood until completely cured of babesiosis.

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Pathophysiology

Babesiosis is a zoonotic disease maintained by the interaction of tick vectors, transport hosts, and animal reservoirs. The primary vectors of the parasite are ticks of the genus Ixodes. In the United States, the black-legged deer tick, Ixodes scapularis (also known as Ixodes dammini; see the image below), is the primary vector for the parasite; in Europe, Ixodes ricinus appears to be the primary tick vector. In each location, the Ixodes tick vector for Babesia is the same vector that locally transmits Borrelia burgdorferi, the agent implicated in Lyme disease.

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Ixodes scapularis, tick vector for babesiosis. Image courtesy of Centers for Disease Control and Prevention.

I scapularis has 3 developmental stages—larva, nymph, and adult—each of which requires a blood meal for development into the next stage. As a larva and nymph, the tick feeds on rodents (eg, the white-footed mouse, Peromyscus leucopus); however, as an adult, the tick prefers to feed on the white-tailed deer. Female ticks are impregnated while obtaining their blood meal on the deer, with the formation of up to 20,000 eggs. (In Europe, by way of contrast, cattle constitute the primary animal reservoir).

The clinical signs and symptoms of babesiosis are related to the parasitism of RBCs by Babesia. The ticks ingest Babesia from the host during feeding; they then multiply the protozoa in their gut wall and concentrate them in their salivary glands. When they feed again on a new host, they inoculate the new host with Babesia.

Entering the host’s bloodstream during the tick bite, the parasite infects RBCs, and differentiated and undifferentiated trophozoites are produced. Upon infection of the host erythrocyte, mature B microti trophozoites undergo asynchronous asexual budding and divide into 2 or 4 merozoites. As parasites leave the erythrocyte, the membrane is damaged. The precise mechanism of hemolysis is unknown.

Babesia species in the host erythrocyte range from 1 to 5 µm in length. B microti measures 2 × 1.5 µm, B divergens measures 4 × 1.5 µm, and B bovis measures 2.4 × 1.5 µm. As noted, the organisms are pear-shaped, oval, or round. Their ring form and peripheral location in the erythrocyte frequently lead to their being mistaken for Plasmodium falciparum. However, they differ from P falciparum in that the schizogony is asynchronous and massive hemolysis does not occur.

Alterations in RBC membranes cause decreased conformability and increased RBC adherence, which can lead to development of noncardiac pulmonary edema and acute respiratory distress syndrome (ARDS) among those severely affected.^[1]

Fever, hemolytic anemia, and hemoglobinuria may result from Babesia infection. As with malaria, RBC fragments may cause capillary blockage or microvascular stasis, which explains liver, splenic, renal, and central nervous system (CNS) involvement. As with malaria, cells of the reticuloendothelial system (RES) in the spleen remove damaged RBC fragments from the circulation. RBC destruction results in hemolytic anemia.

The spleen offers a critical host defense against babesiosis, as suggested by the higher incidence and greater severity of babesiosis in asplenic patients. The spleen traps the infected erythrocytes, and their ingestion by the macrophages follows.

Complement activation by Babesia may lead to the generation of tumor necrosis factor (TNF) and interleukin-1 (IL-1). Decreased complement levels, increased circulating C1q-binding activity, and decreased C4, C3, and CH50 levels are observed in patients with babesiosis. The generation of these primarily macrophage-produced mediators may explain many of the clinical features, such as fever, anorexia, arthralgias, myalgias, and the fulminant shock syndrome of bovine babesiosis.

Babesiosis elicits a B-cell response and a T-cell response. Patients with acute babesiosis have an increase in T-suppressor lymphocytes, T-cytotoxic lymphocytes, or both and decreased responses to lymphocyte mitogens with a polyclonal hypergammaglobulinemia.

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Etiology

Babesiosis is an infection caused by parasites of the Babesia genus. It is a zoonosis that is transmitted from vertebrates to humans through the bite of a tick from the Ixodidae family (I scapularis in the United States, I ricinus in Europe). Ixodes ticks are small and differ from the large Dermacentor ticks that transmit Rocky Mountain spotted fever (RMSF) and ehrlichiosis.

More than 100 species of Babesia exist, but only a small number of them are known to be responsible for the majority of symptomatic disease. The causative agent of babesiosis varies according to geographic region.

In the United States, human infection with Babesia is primarily due to the rodent strain B microti, found mostly in northeastern and midwestern states. A few cases have been reported in Missouri, California, and Washington and are found to be caused by Babesia -like agents named after their geographic location: MO-1 (Missouri; closely related to B divergens), CA-1 (California), and WA-1 (Washington; also known as CA5 and Babesia duncani).

In Europe, the causative agent of babesiosis is typically the cattle strain B divergens, though B microti and B microti -like agents have been identified. Another cattle strain found in Europe, B bovis, also causes disease in humans on occasion.

Tick life cycle

The I scapularis life cycle requires 2 years for completion, beginning from egg deposition in the spring. The white-footed mouse is the primary enzootic reservoir. After feeding on infected white-footed mice, the tick larvae become infected with B microti. The tick larvae are maintained as the tick develops from the larval phase to the nymphal phase. This development takes 1 year (ie, until the next spring).

Nymphs infected with B microti may transmit the Babesia organisms to other mice or rodents or to a human host. Nymphs feed for 3-4 days on white-footed mice or rodents and mature into adults the following fall.

Adult Ixodes tick populations are maintained in white-tailed deer. The adults mate and feed on the deer during the spring; they then deposit their eggs and die. The white-footed mouse is necessary to perpetuate the Babesia organisms, and the deer is needed to perpetuate the Ixodes tick population.

Larvae, nymphs, and adult ticks all may infect humans, but the nymph is the primary vector of B microti infection in humans.

Risk factors

Babesia parasites from rodents (primarily the white-footed deer mouse but also the field mouse, vole, rat, and chipmunk) are transmitted to humans during tick bites in endemic areas. Babesiosis is understandably more prevalent during the periods of tick activity, such as spring and summer.

Although rodents are infected with Babesia, the white-tailed deer does not carry the organism. B microti is transmitted from the larval phase of I scapularis to the nymphal phase (transstadial transmission) but not transovarially. Human infection is primarily produced by the bite of an infected nymph during a blood meal. Restocking of deer populations and curtailment of hunting has increased deer herds in certain areas. The proximity of deer, mouse, and tick create the conditions for human infection.

Several reported cases of infection via blood transfusions from donors who lived in or traveled to an endemic area have been documented.^{[3, 4]} All of these cases have occurred in the United States, with the exception of 1 patient in Canada (acquired from a donor who became infected while in the United States) and 1 in Japan. The incubation period in transfusion-associated disease appears to be 6-9 weeks. The rate of acquiring B microti from a unit of packed RBCs has been estimated to be 1 in 600-1800 in endemic areas.

Case reports of transplacental or perinatal transmission have been documented. Transplacental transmission has also occurred rarely.

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Epidemiology

United States statistics

Human babesiosis is endemic in the northeastern coastal region of the United States, particularly Nantucket Island, Martha’s Vineyard, and Cape Cod (Massachusetts); Block Island (Rhode Island); and eastern Long Island,^[5] Shelter Island, and Fire Island (New York). Disease prevalence in Cape Cod, as suggested by antibody to B microti, has been reported as 3.7%, whereas on Shelter Island in individuals with a high risk of exposure to ticks, it was 4.4% in June and reached 6.9% by October.

Cases have also been reported from the Connecticut mainland and Washington State. In addition, infections with Babesia species have been reported in New Jersey, Maryland, Virginia, California, Wisconsin, Minnesota, Missouri, Georgia, and Mexico.

An increasing trend over the past 30 years may be the result of restocking of the deer population, curtailment of hunting, and an increase in outdoor recreational activities. Between 1968 and 1993, more than 450 cases of Babesia infections were confirmed in the United States. However, the actual prevalence of this disease is unknown because most infected patients are asymptomatic.

In endemic areas, the organism may also be transmitted by blood transfusion.^{[6, 7, 8, 9, 10, 11]}

International statistics

Babesiosis occurs in areas of Europe and Asia, where the tick vector and vertebrate host reside, and it occurs in healthy as well as asplenic persons.^[12] On the whole, however, it is rare in Europe. Since 1957, when the first case of human babesiosis was reported in an asplenic farmer from the former Yugoslavia, approximately 40 cases have been reported, mostly in Ireland, the United Kingdom, and France. All of the cases involved bovine Babesia and occurred in individuals who were splenectomized.

Sporadic case reports of babesiosis in Japan, Korea, China, Mexico, South Africa, and Egypt have also been documented. One report describes human Babesia infection in Columbia.

Age-, sex-, and race-related demographics

Although persons of any age can be affected by babesiosis, clinically ill patients with intact spleens are usually aged 50 years or older, which suggests that age plays a factor in the severity of the clinical response. Patients with babesiosis who were previously healthy individuals are generally older (mean, >60 years) than those who had previous medical problems (mean, 48 years). Vannier et al suggested that the age-associated decline in resistance to B microti is genetically determined.^{[1, 2]}

Babesiosis has no predilection for sex or race.

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Prognosis

Babesiosis has a spectrum of severity, which may be divided into 3 distinct parts as follows^[1] :

• Asymptomatic infection
• A mild-to-moderate viral-like syndrome
• Severe disease with a fulminant course resulting in death or a persistent relapsing course

Babesiosis in otherwise healthy hosts produces an acute infectious disease that resembles malaria. Most cases of babesiosis are subclinical or are mildly symptomatic. Babesiosis may continue for more than 2 months after treatment; asymptomatic infections can persist silently for months to years. Patients with positive smears or positive polymerase chain reaction (PCR) test results more than 3 months after initial treatment should be treated again, regardless of the presence or absence of seizures.

In healthy individuals with intact spleens, babesiosis is rarely fatal; however, in patients who are asplenic, babesiosis is generally quite severe and is associated with substantial mortality. Asplenic patients have a more fulminant and prolonged clinical course and may have overwhelming infection that results in death.^[13] In a 1998 review by White et al, 9 of 139 (6.5%) patients who were hospitalized with babesiosis in New York State from 1982-1983 died.^[14]

In the United States, the prognosis for babesiosis is excellent; most patients recover spontaneously. About 25% of adults and 50% of children infected with Babesia are asymptomatic, improve spontaneously without treatment, or both. Fewer than 10% of US patients with babesiosis have died, and most of these have been elderly or asplenic.

In Europe, however, babesiosis is a life-threatening disease. Most symptomatic European patients are asplenic, which contributes to a poor prognosis. More than 50% of patients with babesiosis in Europe become comatose and die. About 83% of infected patients are asplenic.

Deaths have been reported from transfusion-transmitted babesiosis within the immunocompromised population in areas where Babesia infection is not endemic.^[15]

Approximately 20% of patients with babesiosis are co-infected with Lyme disease. The symptoms experienced by these patients are more severe symptoms and last longer than those experienced by patients who have either disease alone.

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History

The history of babesiosis includes fever and chills. Patients with babesiosis have symptoms similar to those of malaria. Symptoms are related to the degree of red blood cell (RBC) parasitemia. The spectrum of disease manifestation is broad, ranging from a silent infection to a fulminant malarialike disease that results in severe hemolysis and, occasionally, death.

In the United States, infection with B microti in otherwise healthy individuals generally remains subclinical; however, symptomatic infection is common in asplenic patients, older patients, and patients with underlying medical conditions, including human immunodeficiency virus (HIV) infection. Because bovine babesiosis due to B divergens and B bovis in Europe mostly occurs in patients who are asplenic, such infections are generally clinically overt and frequently fatal.

Patients typically report a history of travel to an endemic area between May and September. This is the period during which the Ixodes tick is in its infectious nymph stage. Because the nymph, the primary vector, is only 2 mm in diameter when engorged, most patients do not recall a tick bite. The incubation period after the tick bite is usually 1-3 weeks but may occasionally be as long as 9 weeks.

Initial symptoms begin gradually and are nonspecific. Common symptoms include the following:

• Malaise
• Fatigue
• Anorexia
• Shaking chills
• Fever – This may be sustained or intermittent, and temperatures may be as high as 40°C
• Headache
• Myalgias
• Arthralgias
• Nausea
• Vomiting
• Abdominal pain
• Depression and emotional lability
• Dark urine
• Photophobia, conjunctival injection, sore throat, or cough – These are less common symptoms
• Neck stiffness
• Altered sensorium
• Shortness of breath

In a series of 139 patients who were hospitalized with babesiosis in New York, the following were the most common symptoms^[14] :

• Fatigue, malaise, and weakness (91%)
• Fever (91%)
• Shaking chills (77%)
• Diaphoresis (69%)

In some untreated patients, symptoms of babesiosis may last for months. Subclinical infections may spontaneously recrudesce after splenectomy and after immunosuppressive therapy.

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Physical Examination

Physical findings may vary, depending on the severity of disease. Most patients with babesiosis have few, if any, physical findings. Fever is generally present. A minority of patients have jaundice and splenomegaly.

Hepatomegaly may be noted. Petechiae may be present in a few patients. Ecchymoses have been noted occasionally. A rash similar to erythema chronicum migrans has been described, but this probably represents intercurrent Lyme disease. Slight pharyngeal erythema may occur. Babesiosis has been associated with shock and acute respiratory distress syndrome (ARDS). Rigors and altered mental status may be noted.

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Complications

The complications of babesiosis are related to the degree of intravascular hemolysis. The main complications include jaundice, hemoglobinuria, and potential renal failure. The following may be observed:

• Shock
• Death
• Relapse
• Spontaneous splenic rupture^{[16, 17]}

Patients who have undergone splenectomy are unable to clear infected RBCs; this inability results in higher levels of parasitemia, eventually leading to hypoxemia and subsequent risk of cardiopulmonary arrest.

In severe cases, damage to RBC membranes, decreased deformability, and cytoadherence to capillaries and venules lead to pulmonary edema and respiratory failure. These respiratory problems begin after treatment has been initiated, at a time when intraerythrocytic death of parasites has been postulated to cause sensitivity to endotoxin. ARDS may occur through mechanisms such as endotoxemia, complement activation, immune complex deposition, cytoadherence, microemboli, and disseminated intravascular coagulation.

Cardiac complications of babesiosis include the following:

• Myocardial infarction
• Congestive heart failure

Renal complications of babesiosis include the following:

• Renal insufficiency
• Renal failure

Postsplenectomy patients may experience hemophagocytic syndrome, acute renal failure, and generalized seizures. Coma can occur, possibly as a consequence of severe sepsis, ARDS, or multiple organ dysfunction syndrome (MODS). Coinfection with Lyme disease is a possible complication.

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Approach Considerations

Babesiosis should be considered in patients who have a malarialike illness in areas endemic for Babesia infection; however, it can be quite difficult to diagnose. Although the index of suspicion should be high in such areas, patients with babesiosis have few, if any, localizing signs to suggest the disease.

Various direct and indirect tests may be useful for diagnosis (see below), though the results of laboratory studies may be unremarkable in individuals who are asymptomatic. Confirmation of the diagnosis depends on the degree of parasitemia and on the expertise and experience of the laboratory personnel. All of the findings in babesiosis are nonspecific, and only the demonstration of Babesia in the peripheral smear can rapidly confirm the diagnosis.

Lactate dehydrogenase (LDH) measurement and a properly stained peripheral blood smear yield the most useful results in patients with suspected babesiosis who have a malarialike illness. Quantitatively stained buffy-coat smears concentrate white blood cells (WBCs) and increase the likelihood of demonstrating Babesia in the peripheral blood. As with malaria, multiple peripheral-stained thin smears or stained buffy-coat preparations may be necessary to detect low levels of Babesia parasitemia.

Consider the possibility of coinfection with Lyme disease because the 2 organisms share the same tick vector (I scapularis). Coinfection often results in increased duration and severity of illness.

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Serum Cellular Evaluation

A complete blood count (CBC) with differential should be performed. Mild-to-severe hemolytic anemia, lymphopenia, and thrombocytopenia are the typical findings in babesiosis. Decreased serum haptoglobin levels^[1] and elevated reticulocyte counts are noted. Atypical lymphocytes may be present, as they are in malaria, and the number of atypical lymphocytes is not related to the degree of parasitemia or the severity of illness.

The following may be observed in patients with babesiosis:

• The percentage of red blood cells (RBCs) parasitized in clinical cases is usually 1-10% but has ranged from less than 1% to 85%
• The total leukocyte count may be within the reference range or mildly decreased
• The erythrocyte sedimentation rate (ESR) may be elevated
• Direct Coombs test results may or may not be positive

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Peripheral Blood Smears

Babesiosis is usually diagnosed by microscopic examination of Giemsa-stained or Wright-stained thin or thick blood smears (see the images below). The ability to identify babesiosis depends on the expertise and experience of the microbiologist or physician and the degree of parasitemia.

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Blood smear showing Babesia species in erythrocytes. Image courtesy of Centers for Disease Control and Prevention.

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Peripheral smear showing babesiosis.

Most patients with intact splenic function who are mildly to moderately ill with babesiosis have 10% or less of parasitemia in their peripheral blood; patients with asplenia usually have greater degrees of parasitemia (eg, >85%). However, the level of parasitemia does not directly correspond to the severity of disease.

Wright or Giemsa stain on thin blood smears reveals the ring forms of babesiosis.

Wright-stained or Giemsa-stained peripheral blood smears reveal intraerythrocytic ring forms with a central pallor. Stained smears from patients with Babesia infection, in addition to having these intraerythrocytic ring forms, may also demonstrate merozoites arranged in a tetrad configuration resembling a Maltese cross (see the image below). Tetrad forms are pathognomonic of babesiosis. In individuals with asymptomatic infection, smear results may be negative.

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Babesia species, tetrad formation. Image courtesy of Centers for Disease Control and Prevention.

Babesia may be mistaken for malarial parasites, particularly the ring forms of P falciparum. Helpful features that distinguish Babesia from Plasmodium include the following:

• Absence of brownish pigment deposits (hemozoin)
• Lack of synchronous stages (schizonts and gametocytes observed with Plasmodium species)
• Occasional presence of tetrads (see above)

In addition, Babesia varies more in shape and in size and may be observed outside erythrocytes with heavier infestation.

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Serum Chemistry

Serum creatinine measurements should be obtained to assess potential renal insufficiency. Care must be taken to consider other causes of an increased serum creatinine level before ascribing these changes to Babesia infection. Both serum creatinine and blood urea nitrogen (BUN) levels may be elevated.

Liver function tests (LFTs) should be obtained to look for elevated hepatic transaminase (ie, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels, an elevated alkaline phosphatase level, hyperbilirubinemia, and a decreased haptoglobin level. These abnormalities are variably present in patients with babesiosis.

Obviously, the total bilirubin and haptoglobin values reflect the intensity of the infection. Elevation of serum transaminase levels is usually mild and transient. A decreased haptoglobin level suggests a significant degree of intravascular hemolysis.

As with malaria, the diagnosis of babesiosis should be questioned if the serum LDH level is not elevated. Increased LDH levels reflect the degree of parasitemia, the severity of Babesia infection, or both.

Serum protein electrophoresis should be performed. Results usually show a polyclonal gammopathy indicative of B-cell hyperreactivity in response to T-cell suppression by Babesia.

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Serologic Testing

Indirect immunofluorescent antibody

Indirect immunofluorescent antibody (IFA) assay of immunoglobulin M (IgM) or immunoglobulin G (IgG) B microti titers can be used to make a serologic diagnosis of babesiosis. This test is considered the standard for serologic detection of B microti infection. An IgM titer of 1:64 or greater is considered positive; a titer of 1:32 or less indicates prior infection. Increased IgG Babesia titers indicate past exposure rather than current infection.

An IgM titer of 1:256 or higher or a greater than 4-fold increase in the titer is considered diagnostic of recent B microti infection (though the correlation between titer and symptom severity is poor). Most patients with an active infection develop serum titers of 1:1024 or higher within a few weeks. Antibody titers then decline slowly over a period of months to 1:256 or lower. Cross-reactions may occur in serum specimens from patients with malaria infections.

Serologic studies that test for B microti do not detect infections due to other strains of Babesia (eg, B divergens, B bovis, B duncani, and B gibsoni) .

Because of the antigenic differences, IFA testing for B microti infections does not detect the WA-1 (B duncani) and MO-1 strains. Accordingly, individuals whose exposure could have occurred on the West Coast of the United States should be tested for antibodies to WA-1 .

Immunoblot assay

For the diagnosis of babesiosis, immunoblot antibody testing has sensitivity and specificity comparable to those of IFA testing. Potential advantages of immunoblot assays over IFA assays include the lack of a need for concentrated serum samples and the relative ease of use (because they can be performed by generalist technicians as opposed to the trained microscopists required for IFA testing).

Enzyme-linked immunosorbent assay

The enzyme-linked immunosorbent assay (ELISA) IgM Lyme test is used in patients with suspected babesiosis because of the high (25%) incidence of coinfection with Lyme disease. Coinfection increases the severity of disease; therefore, it is important to diagnose and treat both infections.

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Hamster Inoculation

When peripheral blood smear and laboratory results are equivocal, the diagnosis may be facilitated by hamster (or gerbil) inoculation. Suspected B microti infection can be confirmed through intraperitoneal inoculation of 1 mL of ethylenediaminetetraacetic acid (EDTA) whole blood from the patient into the peritoneum of a golden hamster, then performing an antibody analysis of the animal’s blood. For suspected B divergens infection, a gerbil is used; this organism replicates readily in gerbils.

The main disadvantage of this test is that the animal must be checked periodically over a period of 6-8 weeks, which makes the test time- and labor-intensive and renders it impractical for rapid diagnosis.

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Polymerase Chain Reaction Assay

A polymerase chain reaction (PCR)–based diagnostic assay has been reported that appears to hold great promise for increasing the detection rate of very low-level parasitemia. Persistence of antibody titers for B microti has been shown to correlate with the detection of babesial DNA by PCR.^[18] Krause et al reported the detection of babesial DNA by PCR for as long as 27 months after untreated infection.^[19]

Compared with peripheral smear evaluation and hamster inoculation, PCR testing is more sensitive and equally specific. It may be useful in monitoring the infection, though it cannot differentiate between acute or active forms of babesiosis and chronic forms of the disease. In particular, PCR testing may be used to help diagnose recrudescent Babesia infection in patients who have previously had babesiosis or those whose treatment is of questionable effectiveness.

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Other Tests

Urinalysis

Urinalysis should be performed to check for hemoglobinuria. The degree of hemoglobinuria is related to the intensity of the Babesia infection. Urinalysis may also reveal proteinuria, and a dark color may be present.

Chest radiography

Chest radiography may be indicated for patients with respiratory complications, such as suspected pneumonia or acute respiratory distress syndrome (ARDS).

Bone marrow biopsy

Because of the possibility of hemophagocytic syndrome, bone marrow biopsy is indicated in patients whose laboratory studies reveal pancytopenia and whose physical examination reveals hepatosplenomegaly, fever, coagulopathy, or lymphadenopathy.

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Approach Considerations

Suspicion of babesiosis in a patient with a history of exposure in an endemic area, tick bite, fever, chills, and fatigue is crucial. Peripheral blood smear or immunologic testing (see Workup) is necessary to make the diagnosis. A complete blood count (CBC) count with differential is important for determining the severity of infection.

Patients with congenital or acquired asplenia should be expected to have severe or fulminant babesiosis. In patients with fever of unknown origin (FUO), consider babesiosis as a diagnosis if the patient lives in or has traveled to an endemic area or received a blood transfusion in the past.^[20]

If the patient is otherwise healthy and asymptomatic, no treatment is required. Most of the otherwise healthy patients infected by B microti appear to have a mild illness and recover without specific chemotherapy; however, treatment is recommended for all diagnosed cases to prevent sequelae and potential transmission through blood donation.

Immediately start elderly, immunocompromised, or asplenic patients on a combination treatment regimen of intravenous (IV) clindamycin and oral quinine or IV atovaquone and IV azithromycin to avoid acute renal failure. Combination therapy with clindamycin and quinine or atovaquone and azithromycin is more effective than either atovaquone or azithromycin alone. Do not give quinine to pregnant patients.

Intubation and mechanical ventilation may be required for patients who develop respiratory distress or failure.

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Pharmacologic Therapy

In asymptomatic patients with positive results from peripheral smears or polymerase chain reaction (PCR) testing, the studies should be repeated and a course of treatment started if parasitemia persists for more than 3 months. Additionally, patients who were initially treated may require repeat treatment if repeat smears or PCR assays are positive more than 3 months after initial therapy.

In symptomatic patients, antibiotic and antimalarial therapy should be started immediately after diagnosis to reduce the level of parasitemia. The standard treatment has been a combination of clindamycin (20 mg/kg/day for children; 300-600 mg IV or intramuscularly [IM] every 6 hour for adults) and oral quinine (25 mg/kg/day for children; 650 mg every 6-8 hours for adults) administered for 7-10 days. However, this regimen occasionally fails, and patients report frequent side effects, including tinnitus, impaired hearing, and diarrhea.

Consequently, a drug regimen consisting of atovaquone and azithromycin is now first-line treatment for mild-to-moderate disease and has been shown to be effective, especially when clindamycin and quinine fail.

In a prospective nonblinded randomized study, Krause et al found that atovaquone (750 mg every 12 hours) plus azithromycin (500 mg on day 1 and 250 mg/day thereafter) was as effective as clindamycin (600 mg every 8 hours) plus quinine (650 mg every 8 hours) in producing a clinical response and clearing parasitemia.^[21] All patients were treated for 7 days. Adverse effects were reported by 15% of the atovaquone-azithromycin group and 72% of the clindamycin-quinine group.

The combination of clindamycin, doxycycline, and azithromycin was successfully used in a patient who was allergic to quinine.

A patient with acquired immune deficiency syndrome (AIDS) and babesiosis failed treatment with azithromycin and atovaquone followed by quinine and clindamycin. The addition of atovaquone-proguanil to the treatment regimen led to cure.^[22]

One report listed 3 highly immunocompromised patients who received a subcurative course of azithromycin-atovaquone, which led to the development of resistance to this regimen.^[23]

For patients with severe symptoms, clindamycin and quinine remain the first line of treatment.^[1] Parasitemia may persist despite treatment with either of the drug regimens described above. In areas endemic for Lyme disease, physicians should consider treating for Lyme disease empirically.

Immunocompromised individuals who are infected by B microti are at risk for persistent relapsing illness. Such patients generally require antibabesial treatment for 6 weeks or longer to achieve cure, including 2 weeks after parasites are no longer detected on blood smears.^[24]

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Exchange Transfusion and Supportive Care

Exchange transfusion is employed in patients who are profoundly ill with high levels of parasitemia and hemolysis. In severe cases of babesiosis—as demonstrated by high parasitemia (>10%), significant hemolysis, or renal, hepatic, or pulmonary dysfunction—it may be lifesaving. When used concurrently with chemotherapy, exchange transfusion reduces the level of parasitemia and may remove toxic erythrocyte, babesial, or macrophage-produced factors.

Patients with severe babesiosis need to be hospitalized. In addition to receiving anti-Babesia treatment, they may require supportive care. Critically ill patients should be transferred to the intensive care unit (ICU). Patients with mild-to-moderate babesiosis who are discharged from the hospital should undergo the same laboratory tests as hospitalized patients.

Patients being treated for babesiosis should be monitored clinically, and serial blood smears should be obtained to document the degree of parasitemia and the effectiveness of therapy. Serial CBC counts may be obtained to assess the reticulocyte response and evaluate decrease in the hemolytic process. Be alert for the possibility of hemophagocytic syndrome.

Monitor the level of oxygenation, and watch for the development of respiratory complications after the initiation of treatment in patients who present with respiratory complaints. Respiratory distress may be due to endotoxin sensitivity; endotoxin release often results from medication-induced intraerythrocytic death of the parasites. Mechanical ventilation may be necessary in patients with severe disease.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity, to prevent complications, and to eradicate the infection. A combination of an antiprotozoal agent and an antibiotic—clindamycin plus quinine or, alternatively, atovaquone plus azithromycin—is used to treat all patients in order to prevent sequelae and potential transmission through blood donation. Other regimens have been reported in isolated case reports.

The combination of clindamycin and quinine is used to treat Babesia infection. Quinine inhibits the growth of the parasite by increasing the pH within intracellular organelles and possibly by intercalating itself into the parasite’s DNA. Because quinine alone is ineffective in this setting, it must be used in conjunction with clindamycin.

Clindamycin is a lincosamide used to treat serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

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Quinine (Qualaquin)

• Dosing, Interactions, etc.

Clinical Context:  Quinine is a schizonticide. It inhibits the growth of the parasite by increasing the pH within intracellular organelles and possibly by intercalating itself into the DNA of the parasite. It is used in combination with clindamycin.

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Antiprotozoal Agents

Clinical Context:  Atovaquone is a hydroxynaphthoquinone that inhibits the mitochondrial electron transport chain by competing with ubiquinone at the ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone results in inhibition of nucleic acid and adenosine triphosphate (ATP) synthesis in the parasites. This agent is used in combination with azithromycin.

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Class Summary

Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Cinchona alkaloids (eg, quinine) are effective in eradicating the parasite.

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Clindamycin (Cleocin)

Clinical Context:  Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer RNA (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. It is administered in combination with quinine.

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Azithromycin (Zithromax, Zmax)

• Dosing, Interactions, etc.

Clinical Context:  Azithromycin is one of the newer macrolide antibiotics. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Plasma concentrations of azithromycin are very low, but tissue concentrations are much higher, making this agent valuable in the treatment of infections caused by intracellular organisms. Azithromycin has a long tissue half-life. It is administered in combination with atovaquone to treat mild-to-moderate microbial infections.

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Doxycycline (Vibramycin, Doryx, Monodox)

• Dosing, Interactions, etc.

Clinical Context:  The combination of clindamycin, doxycycline, and azithromycin was successfully used in a patient who was allergic to quinine. This agent is a bacteriostatic drug that interferes with bacterial protein and cell-wall synthesis during active multiplication by binding to the 30S ribosome. For severe cases, administer intravenously (IV); for outpatients, oral administration (PO) is preferred.

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Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

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