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]
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:
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.
Blood smear showing Babesia species in erythrocytes. Image courtesy of Centers for Disease Control and Prevention.
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:
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Absence of brownish pigment deposits (hemozoin)
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Lack of synchronous stages (schizonts and gametocytes observed with Plasmodium species)
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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]
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.
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]
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.
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]
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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Peripheral smear showing babesiosis.
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Ixodes scapularis, tick vector for babesiosis. Image courtesy of Centers for Disease Control and Prevention.
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Blood smear showing Babesia species in erythrocytes. Image courtesy of Centers for Disease Control and Prevention.
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Babesia species, tetrad formation. Image courtesy of Centers for Disease Control and Prevention.
