Babesiosis

Background

Babesiosis is a tick-borne, malaria-like illness caused by species of the intraerythrocytic protozoan Babesia. Humans are incidental hosts for Babesia when bitten by nymph or adult ticks. Babesia infection is most commonly seen in the north midwestern and northeastern United States. It also be found throughout the world in certain parts of Europe, Asia, Africa, and South America.^[1]

Human babesiosis is a zoonotic infection in which ticks transmit Babesia organisms from a vertebrate reservoir to humans^{[1, 2]} ; humans are typically dead-end hosts. In the United States, most infections are caused by Babesia microti, a species commonly found in mice. Other species known to infect humans include Babesia duncani, Babesia divergens, Babesia venatorum, and Babesia crassa.^[3]  

Babesia species and organisms of the closely related genus Theileria parasitize the erythrocytes of wild and domestic animals.These parasites are members of the order Piroplasmida, named for the pear-shaped forms found within infected red blood cells (RBCs).^[4]

Over 2000 cases of babesiosis were reported in the United States in 2018.^[5]  In healthy individuals, most infections are asymptomatic. 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.^[3]

Babesiosis can be 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 laboratory personnel.^{[4, 6]}

Most patients infected by B microti who are otherwise healthy appear to have a mild illness and typically recover without specific chemotherapy.  Asymptomatic patients do not necessarily require treatment^[7] ; the decision to treat should be an individualized one. For symptomatic cases, treatment is recommended. In addition, patients should be advised to take precautions against tick exposure and to refrain from donating blood until 2 years from the time of a reactive nucleic acid test result for Babesia.^{[6, 8]}

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Pathophysiology

Babesiosis is a zoonotic disease maintained by the interaction of tick vectors, transport hosts, and animal reservoirs.^[9] The primary vectors of the parasite are ticks of the genus Ixodes. In the United States, the black-legged deer tick, Ixodes scapularis (I scapularis; also known as Ixodes dammini), is the primary vector for the parasite; in Europe, Ixodes ricinus appears to be the primary tick vector.^[10] 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 primarily feeds on rodents (eg, the white-footed mouse, Peromyscus leucopus); however, as an adult, the tick prefers to feed on the white-tailed deer, the primary host in the United States. Female ticks are impregnated while obtaining their blood meal on the deer, with the formation of up to 20,000 eggs. In contrast, cattle constitute the primary animal reservoir in Europe.

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, producing differentiated and undifferentiated trophozoites. 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 noncardiogenic pulmonary edema and acute respiratory distress syndrome (ARDS) among those severely affected.^{[1, 11]}

Fever, hemolytic anemia, and hemoglobinuria may result from Babesia infection. As with malaria, RBC fragments may cause capillary blockage or microvascular stasis, which could explain liver, splenic, renal, and central nervous system (CNS) involvement. Animal studies have shown that increased cytoadherence of infected RBCs could cause these vascular blockages, though further research is needed.^[9]  As in malaria, cells of the reticuloendothelial system (RES) in the spleen remove damaged RBC fragments from the circulation. RBC destruction results in hemolytic anemia. The amount of hemolysis does not seem to be directly related to the degree of parasitemia, though the cause is unclear.^[11]

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 macrophages follows. Additionally, hypersplenism can lead to platelet sequestration which causes thrombocytopenia.^[11]

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, including 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 may have an increase in T-suppressor lymphocytes and/or T-cytotoxic lymphocytes and a decreased response 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 (most commonly 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 north midwestern states. A few cases have been reported in Missouri, California, and Washington. These are 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 B. 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. China and some European countries have also reported B venatorum as a cause of babesiosis. There are multiple other species that are under investigation.^[3]

Tick life cycle

The I scapularis life cycle takes 2 years to complete, beginning with 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 then 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 other 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. 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. 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 may all infect humans, but the nymph is the primary vector of B microti infection.

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 through tick bites in endemic areas. As such, babesiosis is more prevalent during the periods of high tick activity, such as spring and summer.  Restocking of deer populations and curtailment of hunting has increased deer herds in certain areas. The proximity of deer, mouse, and tick creates 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.^{[12, 13]}  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 also been documented.^[3]

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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,^[14] Shelter Island, and Fire Island, New York.  Disease prevalence in Cape Cod, as suggested by antibodies 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.

Babesiosis was a reportable condition in 40 out of 50 states in 2018.  Of those, 28 states reported cases of babesiosis during that year. Most (86%) of the 2,161 cases were reported by 7 states: Connecticut, Massachusetts, New Jersey, Rhode Island, New York, Minnesota, and Wisconsin.^[5]

The incidence of babesiosis has increased since 2004.^[15]  This is thought to be the result of restocking of the deer population, curtailment of hunting, and an increase in outdoor recreational activities; however, the prevalence of this disease is unknown because most infected patients are asymptomatic.

In endemic areas, the organism may also be transmitted by blood transfusion.^{[3, 16, 17, 18, 19, 20, 21]}

International statistics

A 2022 systematic review and meta-analysis found an overall pooled estimate (PE) of 2.23% for Babesia infections in humans. The PEs varied significantly by continent, with North America at 1.54% and Europe at 4.17%. Factors such as country income levels, diagnostic methods, study periods, sample sizes, Babesia species, and targeted populations showed PEs ranging from 0.43% to 7.41%. B microti was the most widely distributed and predominant species in North America, whereas B divergens was primarily reported in Europe. Eight Babesia species were identified in humans globally, with the highest prevalence in Europe and lower middle-income countries, particularly among individuals with a history of tick bites. To address this growing public health threat, recommendations include implementing tick control measures in human habitats, encouraging protective clothing for those at risk, and screening transfusion blood in endemic regions.^[22]

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, suggesting that age plays a factor in the severity of disease. 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 known 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 may produce an acute infectious condition that resembles malaria. However, most cases of babesiosis are subclinical or only mildly symptomatic. 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 and improve spontaneously without treatment. Fewer than 10% of US patients with babesiosis have died; most of these have been elderly or asplenic.

In patients who are asplenic, babesiosis can be quite severe and is associated with substantial mortality. Asplenic patients tend to have a more fulminant and prolonged clinical course.^[23]  Highly immunocompromised patients are at a higher risk for complications such as acute respiratory distress syndrome, shock, warm autoimmune hemolytic anemia, heart failure, and death.^[3]  In a 1998 review, 9 of 139 (6.5%) patients who were hospitalized with babesiosis in New York State from 1982-1983 died.^[24]  

Immunocompromised patients are at a higher risk of relapse, especially if they have HIV with acquired immunodeficiency syndrome (AIDS), if they are transplant patients on immunosuppression, if they are receiving rituximab, or if they have malignancy and asplenia.^[3]

In Europe, babesiosis often comes from B divergens, which can cause life-threatening infection. About 83% of infected European patients are asplenic, contributing to a poor prognosis. More than 50% of patients with babesiosis in Europe become comatose and die.

Deaths have been reported from transfusion-transmitted babesiosis within the immunocompromised population in areas where Babesia infection is not endemic.^[25]  The mortality rate of B microti infection from a transfusion is about 20%.^[3]

Approximately 10-20% of patients with babesiosis are co-infected with Lyme disease.^[3] The symptoms experienced by these patients are more severe and prolonged than symptoms experienced by patients who have either disease alone. Babesia co-infection should be considered when a patient with Lyme disease does not respond to typical therapy or when a patient with Lyme disease has atypical symptoms.

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History

The spectrum of babesiosis manifestations is broad, ranging from a silent infection to a fulminant malaria-like disease with fever and chills that results in severe hemolysis and, occasionally, death. Symptoms are thought to be related to the degree of red blood cell (RBC) parasitemia, though this is not always the case.

In the United States, infection with Babesia microti in otherwise healthy individuals often remains subclinical; however, symptomatic infection is common in asplenic, elderly, and immunocompromised patients. In Europe, because bovine babesiosis due to Babesia divergens and Babesia bovis mostly occurs in patients who are asplenic, 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.

·       Diaphoresis

·       Headache

·       Myalgias

·       Arthralgias

·       Nausea

·       Vomiting

·       Abdominal pain

·       Depression and emotional lability

·       Dark urine

·       Neck stiffness

·       Altered sensorium

·       Shortness of breath

·       Less commonly, photophobia, conjunctival injection, sore throat, or cough

In a series of 139 patients who were hospitalized with babesiosis in New York, the following were the most common symptoms^[24] :

·       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 exam findings vary with the severity of disease. Most patients have few, if any, physical findings. Fever is generally present. A minority of patients have jaundice, splenomegaly, or hepatomegaly.  Petechiae may be present in a few patients, and ecchymoses have been noted occasionally. A rash similar to erythema chronicum migrans has been described, but this probably represents intercurrent Lyme disease. Rigors and altered mental status may be seen. Babesiosis has also been associated with shock and ARDS.  

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Complications

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

·       Shock

·       Spontaneous splenic rupture^{[26, 27]}

·       Relapse

·       Death

Cardiac complications of babesiosis include the following:

·       Myocardial infarction

·       Congestive heart failure

Renal complications of babesiosis include the following:

·       Renal insufficiency

·       Renal failure

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 can begin after treatment has been initiated; researchers have postulated that this is due to intraerythrocytic death of parasites prompting sensitivity to endotoxin. ARDS may occur through mechanisms such as endotoxemia, complement activation, immune complex deposition, cytoadherence, microemboli, and disseminated intravascular coagulation.^{[11, 28]}

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 increased risk of cardiopulmonary arrest. Postsplenectomy patients may also 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).^[28]

Coinfection with Lyme disease is another possible complication.^[29]  More research is needed into whether coinfection with Borrelia burgdorferi causes worse morbidity or mortality than either infection alone.

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Approach Considerations

Babesiosis should be considered in patients who have a malaria-like illness with history of travel to 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.^{[4, 6]}  Guidelines from Infectious Diseases Society of America (IDSA) recommend confirmatory testing for babesiosis with a blood smear or PCR.^[3]

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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.^[3] Atypical lymphocytes may be present, as they are in malaria. The number of atypical lymphocytes is not known to be related to the degree of parasitemia or the severity of illness.^[36]

The following may also be observed in patients with babesiosis:

• The total leukocyte count varies.^[9]
• Direct Coombs test results may or may not be positive.^[11]
• Patients may have decreased serum haptoglobin and elevated reticulocyte counts.^[1]

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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.^[28] The ability to identify babesiosis depends on the expertise and experience of the microbiologist or physician and the degree of parasitemia. Reviewing 200-300 fields under oil immersion increases the sensitivity of this test, but there is no standard number of fields to review.^[3]

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. Tetrad forms are pathognomonic of babesiosis. In individuals with asymptomatic infection, smear results may be negative.

The IDSA defines high-grade parasitemia in babesiosis as levels over 10%.^[3]  Patients with clinical manifestations of babesiosis usually have parasitemia of more than 0.1%, though that degree of infection can be difficult to detect.^[11]  The degree of parasitemia does not necessarily correlate with the severity of disease.

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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.

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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.^[11]  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 

In addition, Babesia varies more in shape and size and may be observed outside erythrocytes in patients with higher levels of parasitemia.

Thick smears can sometimes increase sensitivity due to the increased number of erythrocytes seen on a thick smear; however, Babesia may be easier to detect on thin smears due to the size of the organisms.  It is important to have personnel who are experienced in preparation and review of these smears.^[3]

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Serum Chemistry

Serum creatinine measurements should be obtained to assess potential renal insufficiency. Both serum creatinine and blood urea nitrogen (BUN) levels may be elevated^[9] ; however, care must be taken to consider other causes of acute kidney injury before ascribing these changes to Babesia infection.

Liver enzymes should be obtained to look for elevated hepatic transaminase levels (ie, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), an elevated alkaline phosphatase level, and hyperbilirubinemia. These abnormalities are variably present in patients with babesiosis.^[9]

As with malaria, babesiosis may present with elevated serum lactate dehydrogenase (LDH).^[9] It is unclear whether increased LDH levels reflect the degree of parasitemia or the severity of Babesia infection.

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Serologic Testing

Indirect immunofluorescent antibody

Indirect immunofluorescent antibody (IFA) assays of immunoglobulin M (IgM) or immunoglobulin G (IgG) Babesia microti titers can aid in diagnosis of babesiosis.  However, current IDSA guidelines recommend confirmatory testing for babesiosis with a blood smear or PCR.^[3] . An IgM titer of 1:64 or greater is usually considered positive, while a titer of 1:32 or less could indicate prior infection. IgG Babesia titers of 1:1024 or greater typically suggest active or recent infection.^[3]  A four-fold increase in Babesia IgG titer from the the time of symptom onset to the time of symptom resolution or improvement can aid in confirming the diagnosis of babesiosis. Higher titers do not necessarily indicate more severe infection.

Note that serologic studies that test for B microti do not detect infections due to other species of Babesia (eg, B divergens, B bovis, B duncani, and B gibsoni) due to antigenic differences.^[3]  If testing for B microti is negative but suspicion for babesiosis remains high, consider testing for other strains that are endemic to areas where the patient has traveled. 

IFA for B microti detects antibodies in 88-96% of patients with B microti infection. These antibodies can persist for over a year regardless of whether a patient has had treatment. This can make diagnosis of acute babesiosis more difficult. If a patient has a positive Babesia IFA with negative PCR and/or blood smear, treatment is not recommended since active infection is unlikely.^[3]  

Immunoblot assay

Immunoblot assays for babesiosis are available, but they are not recommended for routine diagnostic purposes.^[3]

Enzyme-linked immunosorbent assay

Enzyme-linked immunosorbent assay (ELISA) has been used to screen the blood supply for Babesia organisms, but it is not routinely used in clinical settings.^[3]

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Hamster Inoculation

Prior to the development of PCR testing for babesiosis, when peripheral blood smear and laboratory results were equivocal, the diagnosis could be facilitated by hamster (or gerbil) inoculation.^[37] This is now mainly done for research purposes. Suspected B microti infection could 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.

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

Polymerase chain reaction (PCR)–based diagnostic assays have increased the detection rate of very low-level parasitemia. PCR is now one of the recommended laboratory tests for diagnosis for babesiosis, the other test being peripheral blood smear evaluation.^[3]  Persistence of antibody titers for B microti has been shown to correlate with the detection of babesial DNA by PCR.^[38]  The detection of babesial DNA by PCR has been reported for as long as 27 months after untreated infection.^[39]

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.

Immunocompromised patients should be monitored for Babesia parasitemia with peripheral blood smears even after they become asymptomatic.  If an immunocompromised patient continues to have symptoms, but their blood smears have become negative, consider PCR testing.^[3]

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Other Tests

Urinalysis

Urinalysis may show hemoglobinuria and proteinuria, and a dark color may be present.^[3]  The degree of hemoglobinuria correlates with the degree of intravascular hemolysis.

Chest radiography

Chest radiography may be indicated for patients with respiratory complications, such as suspected pneumonia or ARDS.

Bone marrow biopsy

Because of the possibility of hemophagocytic syndrome, bone marrow biopsy can be considered in patients whose laboratory studies reveal pancytopenia and whose physical examination reveals hepatosplenomegaly, fever, coagulopathy, or lymphadenopathy.^[11]

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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 PCR is necessary to make the diagnosis.^[3] A complete blood count (CBC) count with differential may be helpful for determining the severity of infection.

Patients with congenital or acquired asplenia can have severe or fulminant babesiosis. In patients with fever of unknown origin (FUO), consider babesiosis as a diagnosis if the patient lives in an endemic area, has traveled to an endemic area, or received a blood transfusion in the past.^[40]

If a patient is otherwise healthy and asymptomatic, no treatment is required.^[3]  Most of the otherwise healthy patients infected by Babesia microti appear to have a mild illness and recover without specific chemotherapy. Asymptomatic, immunocompetent patients do not require monitoring for clearance of parasitemia.

The IDSA recommends starting symptomatic patients on a combination treatment regimen of  atovaquone and azithromycin (first line) or a combination of clindamycin and quinine (alternative therapy).

Immunocompromised patients should be monitored for parasitemia on blood smears until the blood smears are negative, regardless of symptoms.  Symptomatic immunocompetent patients should have blood smears monitored for parasitemia during acute illness. Once symptoms have resolved, the IDSA recommends against monitoring blood smears for parasitemia.^[3]

Intubation and mechanical ventilation may be required for patients who develop respiratory distress or failure. Other supportive care may be necessary in some patients; this could include vasopressors for hypotensive patients, blood transfusions, and dialysis.^[3]

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Pharmacologic Therapy

In asymptomatic, immunocompetent patients with positive results from peripheral smears or polymerase chain reaction (PCR) testing, treatment is not recommended. If a patient is diagnosed after symptoms have resolved, they should not receive treatment unless organisms are seen on peripheral smear for more than one month from the time of acute illness. PCR assays are not recommended for monitoring parasitemia in this patient group since relapse rarely occurs.^[3]

In symptomatic, immunocompetent patients, antimicrobial therapy should be started after confirmed diagnosis to reduce the level of parasitemia. A drug regimen consisting of atovaquone and azithromycin is now first-line treatment and has been shown to be effective.^[3]  Clindamycin plus quinine is an alternative regimen, but it results in far more adverse effects.  

Per the IDSA, the recommended regimens in adults are as follows^[3] :

• • First line: atovaquone 750 mg PO q12h plus azithromycin 500 mg PO on day one, followed by 250 mg PO q24h for 7-10 days
  • Alternative treatment: clindamycin 600 mg PO q8h plus quinine sulfate 542 mg base (equal to 650 mg salt) PO q6-8h for 7-10 days

   

  

   
• • First line: atovaquone 750 mg PO q12h plus azithromycin 500-1000 mg IV q24h until symptoms improve, then convert to step-down therapy 
  • Alternative treatment: Clindamycin 600 mg IV q6h plus quinine sulfate 542 mg base (equal to 650 mg salt) PO q6-8h until symptoms improve, then convert to step-down therapy 

   

  

   
• • First line: atovaquone 750 mg PO q12h plus azithromycin 250-500 mg PO q24h; total course of therapy is usually 7-10 days.  Consider using a higher dose of azithromycin (500-1000 mg) in immunocompromised patients.
  • Alternative treatment: clindamycin 600 mg PO q8h plus quinine sulfate 542 mg base (equal to 650 mg salt) PO q6-8h; total course of therapy is usually 7-10 days.

   

  

   
• • Highly immunocompromised patients include the following:
    • Patients who are receiving or have received rituximab for B-cell lymphoma or autoimmune disease
    • Patients on immunosuppressive regimens for solid organ or bone marrow transplantations or malignancy
    • Patients who have malignancy and are asplenic
    • Patients who have HIV with a CD4 count of less than 200 (AIDS)
  • These patients should receive the regimen for hospitalized adults with acute severe disease, followed by step-down therapy, but treatment must be continued for at least 6 consecutive weeks, and peripheral blood smears should be free of parasites for the 2 final weeks of this period.
  • As previously stated, higher doses of oral azithromycin (500-1000 mg daily) should be considered in these patients when oral azithromycin is appropriate.

   

  

   

Relapse is more common in immunocompromised patients.  If a patient experiences relapse, the IDSA notes that the following regimens have been used with limited evidence:

• Atovaquone + azithromycin + clindamycin
• Atovaquone + clindamycin
• Atovaquone/proguanil + azithromycin
• Atovaquone + azithromycin + clindamycin + quinine

With relapse, higher doses of azithromycin (500 or 1000 mg daily) have been used.^[3]

In children, the following regimens are recommended^[3] :

• • First line: Atovaquone 20 mg/kg/dose (up to 750 mg) q12h PO plus azithromycin 10 mg/kg/dose (up to 500 mg) PO on day one, followed by 5 mg/kg/dose q24h for 7-10 days
  • Alternative treatment: Clindamycin 7-10 mg/kg/dose (up to 600 mg/dose) PO q8h plus quinine sulfate 6 mg base/kg/dose (equivalent to 8 mg salt/kg/dose; up to 542 mg base or 650 mg salt/dose) PO q6-8h for 7-10 days

   

  

   
• • First line: Atovaquone 20 mg/kg/dose (up to 750 mg) q12h PO plus azithromycin 10 mg/kg/dose (up to 500 mg) q24h IV until symptoms improve, then convert to step-down therapy
  • Alternative treatment: Clindamycin 7-10 mg/kg/dose (up to 600 mg/dose) IV q8h plus quinine sulfate 6 mg base/kg/dose (equivalent to 8 mg salt/kg/dose; up to 542 mg base or 650 mg salt/dose) PO q6-8h until symptoms improve, then convert to step-down therapy

   

  

   
• • Atovaquone 20 mg/kg/dose (up to 750 mg) q12h PO plus azithromycin 10 mg/kg/dose (up to 500 mg) PO; total therapy is usually 7-10 days.
  • Clindamycin 7-10 mg/kg/dose (up to 600 mg/dose) PO q8h plus quinine sulfate 6 mg base/kg/dose (equivalent to 8 mg salt/kg/dose; up to 542 mg base or 650 mg salt/dose) PO q6-8h; total therapy is usually 7-10 days.

   

  

   
• • Include the same group of highly immunocompromised patients described above in the adult regimens section.
  • These patients should receive the regimen for hospitalized children with acute severe disease, followed by step-down therapy, but treatment must be continued for at least 6 consecutive weeks, and peripheral blood smears should be free of parasites for the 2 final weeks of this period.

   

  

   
• Relapse regimens in children are similar to the relapse regimens listed above for adults.

A prospective, non-blinded, randomized study found that a seven-day course of 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 salt every 8 hours) in producing a clinical response and clearing parasitemia^[41] ; however, the risk of adverse effects in the clindamycin-quinine group was substantially greater at 72% when compared to the atovaquone-azithromycin group at 15%.

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

Another case report described a patient with acquired immune deficiency syndrome (AIDS) and babesiosis who failed treatment with azithromycin and atovaquone followed by quinine and clindamycin. The addition of atovaquone-proguanil to the treatment regimen led to cure.^[42]

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.^[43]

Parasitemia may persist despite treatment with either of the drug regimens described above. In areas endemic for Lyme disease, physicians should consider coinfection with Lyme disease as a possibility and treat accordingly.^[3]

Immunocompromised individuals who are infected by B microti are at risk for persistent relapsing illness. As previously described, such patients generally require antibabesial treatment for 6 weeks or longer to achieve cure, including a final 2 weeks during which parasites are no longer detected on blood smears.^[44]

Atovaquone is a pregnancy category C drug, azithromycin and clindamycin are both in category B, and quinine has no US FDA pregnancy category as of this writing. Quinine does cross the placenta, but it is sometimes used in patients where the benefit outweighs the risk.

• References

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.^[3] 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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Prevention

There is no vaccine for Babesiosis. Recommendations include implementing tick control measures in human habitats, encouraging protective clothing for those at risk, and screening transfusion blood in endemic regions.^{[7, 22]}

• References

Guidelines Summary

Infectious Diseases Society of America (IDSA)

 The Infectious Diseases Society of America (IDSA) has published guidelines for diagnosing and managing babesiosis. ^[3]

Diagnosis

The IDSA recommends peripheral blood smear examination or polymerase chain reaction (PCR) rather than antibody testing for diagnostic confirmation of acute babesiosis.

The IDSA recommends confirmation of a positive Babesia antibody test with blood smear or PCR before considering treatment.

Management

The IDSA recommends treating babesiosis with the combination of atovaquone plus azithromycin or the combination of clindamycin plus quinine.

The IDSA suggests exchange transfusion using red blood cells in selected patients with severe babesiosis.

The IDSA recommends monitoring Babesia parasitemia during treatment of acute illness in immunocompetent patients using peripheral blood smears. The IDSA recommends against testing for parasitemia once symptoms have resolved in this patient group.

The IDSA suggests monitoring Babesia parasitemia in immunocompromised patients using peripheral blood smears even after patients become asymptomatic and until blood smears are negative. The IDSA suggests PCR testing be considered if blood smears become negative and symptoms persist in the immunocompromised population.

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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—atovaquone plus azithromycin or, alternatively, quinine plus clindamycin—is used to treat symptomatic patients in order to prevent sequelae and potential transmission through blood donation. Other regimens have been reported in isolated case reports.

• References

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.

• References

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.

• References

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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