BABESIOSIS

From:
http://www.dpd.cdc.gov/dpdx/HTML/Babesiosis.htm

Babesiosis:
[Babesia microti] [Babesia divergens]

Causal Agents:
Babesiosis is caused by hemoprotozoan parasites of the genus Babesia. While more than 100 species have been reported, only a few have been identified as causing human infections. Babesia microti and Babesia divergens have been identified in most human cases, but variants (considered different species) have been recently identified. Little is known about the occurrence of Babesia species in malaria-endemic areas where Babesia can easily be misdiagnosed as Plasmodium.

References:
Herwaldt BL, Persing DH, Précigout EA, et al. A fatal case of babesiosis in Missouri: Identification of another piroplasm that infect humans. Ann Intern Med 1996; 124:643-65

Pershing DH, Herwaldt BL, Glaser C, et al. Infection with a Babesia-like organism in northern California. N Engl J Med 1995; 332: 298-303.

Life Cycle:
The Babesia microti life cycle involves two hosts, which includes a rodent, primarily the white-footed mouse, Peromyscus leucopus. During a blood meal, a Babesia-infected tick introduces sporozoites into the mouse host

1. Sporozoites enter erythrocytes and undergo asexual reproduction (budding)

2. In the blood, some parasites differentiate into male and female gametes although these cannot be distinguished at the light microscope level

3. The definitive host is a tick, in this case the deer tick, Ixodes dammini (I. scapularis). Once ingested by an appropriate tick,

4. gametes unite and undergo a sporogonic cycle resulting in sporozoites

5. Transovarial transmission (also known as vertical, or hereditary, transmission) has been documented for “large” Babesia spp. but not for the “small” babesiae, such as B. microti

A. Humans enter the cycle when bitten by infected ticks. During a blood meal, a Babesia-infected tick introduces sporozoites into the human host

6. Sporozoites enter erythrocytes

B. and undergo asexual replication (budding)

7. Multiplication of the blood stage parasites is responsible for the clinical manifestations of the disease. Humans are, for all practical purposes, dead-end hosts and there is probably little, if any, subsequent transmission that occurs from ticks feeding on infected persons.

8.However, human to human transmission is well recognized to occur through blood transfusions.

Note: Deer are the hosts upon which the adult ticks feed and are indirectly part of the Babesia cycle as they influence the tick population. When deer populations increase, the tick population also increases, thus heightening the potential for transmission.

Geographic Distribution:
Worldwide, but little is known about the prevalence of Babesia in malaria-endemic countries, where misidentification as Plasmodium probably occurs. In Europe, most reported cases are due to B. divergens and occur in splenectomized patients. In the United States, B. microti is the agent most frequently identified (Northeast and Midwest), and can occur in non-splenectomized individuals. Two variants, arguably different species, have been reported in the U.S. states of Washington and California (WA1- type and related parasites) and Missouri (MO1).

Clinical Features:
Most infections are probably asymptomatic, as indicated by serologic surveys. Manifestations of disease include fever, chills, sweating, myalgias, fatigue, hepatosplenomegaly, and hemolytic anemia. Symptoms typically occur after an incubation period of 1 to 4 weeks, and can last several weeks. The disease is more severe in patients who are immunosuppressed, splenectomized, and/or elderly. Infections caused by B. divergens tend to be more severe (frequently fatal if not appropriately treated) than those due to B. microti, where clinical recovery usually occurs.

Laboratory Diagnosis:
Diagnosis can be made by microscopic examination of thick and thin blood smears stained with Giemsa. Repeated smears may be needed.

Microscopy:
A: Babesia microti infection, Giemsa-stained thin smear. The organisms resemble Plasmodium falciparum; however Babesia parasites present several distinguishing features: they vary more in shape and in size; and they do not produce pigment. A 67 year old woman, status post-splenectomy, infection probably acquired in Long Island (New York).

Infection with Babesia. Giemsa-stained thin smears. Note in B the tetrad (left side of the image), a dividing form pathognomonic for Babesia. Note also the variation in size and shape of the ring stage parasites (compare B and C), and the absence of pigment. A 6 year old girl, status post splenectomy for hereditary spherocytosis, infection acquired in the US.

Antibody Detection:
Diagnosis of Babesia infection should be made by detection of parasites in patients’ blood smears. However, antibody detection tests are useful for detecting infected individuals with very low levels of parasitemia (such as asymptomatic blood donors in transfusion-associated cases), for diagnosis after infection is cleared by therapy, and for discrimination between Plasmodium falciparum and Babesia infection in patients whose blood smear examinations are inconclusive and whose travel histories cannot exclude either parasite.

The indirect fluorescent antibody test (IFA) using B. microti parasites as antigen detects antibodies in 88-96% of patients with B. microti infection. IFA antigen slides are prepared using washed, parasitized erythrocytes produced in hamsters. Patients’ titers generally rise to greater than or equal to 1:1024 during the first weeks of illness and decline gradually over 6 months to titers of 1:16 to1:256, but may remain detectable at low levels for a year or more. Specificity is 100% in patients with other tick-borne diseases or persons not exposed to the parasite. Cross-reactions may occur in serum specimens from patients with malaria infections, but generally titers are highest with the homologous antigen.

The extent of cross-reactivity between Babesia species is variable. A negative result with B. microti antigen for a patient exposed on the West Coast may be a false-negative reaction for Babesia infection. Individuals whose exposure could have occurred on the West Coast should be tested also for antibodies to the Babesia WA1 species, because of the lack of cross-reactivity with B. microt.

Reference:
Krause PJ, Telford S RI , Ryan R, et al. Diagnosis of babesiosis: Evaluation of a serologic test for the detection of Babesia microti antibody. 1994; J Infect Dis 169:923-926

Molecular diagnosis:
In some infections with intra-erythrocytic parasites, the morphologic characteristics observed on microscopic examination of blood smears do not allow an unambiguous differentiation between Babesia and Plasmodium. Moreover, potential blood donors may have subclinical symptoms and very low parasitemia, undetectable in blood smears. In such cases, the diagnosis can be derived from molecular techniques, such as PCR using the appropriate primers and single-step, or the more sensitive - nested PCR technique. In addition, molecular approaches are very valuable in investigations of new Babesia variants (or species) observed in recent human infections in the US and in Europe.

A: Agarose gel (2%) analysis of a PCR diagnostic test for detection of Babesia microti DNA. PCR was performed using a nested protocol with primers BAB1 and BAB4 (first round) and BAB2 and BAB3 (second round).

Lane S: Molecular base pair standard (50-bp ladder). Black arrows show the size of standard bands.

Lane 1: First step amplification with primers BAB1 and BAB4 of the nested PCR protocol for detection of B. microti in DNA extracted from whole blood. The specimen, serologically positive for B. microti, was submitted to the CDC by the American Red Cross. The red arrow shows the single-step PCR diagnostic band for B. microti (size: 238 bp).

Lane2: Nested PCR with primers BAB2 and BAB3 using as template the product of the first step amplification. The blue arrow shows the nested PCR diagnostic band for B. microti (size: 154 bp). Please note the enhanced sensitivity of B. microti DNA detection with the nested reaction.

Reference:
Persing DH, Mathiesen D, Marshall WF, Telford SR, Spielman A, Thomford JW, Conrad PA. Detection of Babesia microti by polymerase chain reaction. J Clin Microbiol 1992;30:2097-103.

Treatment:
Treatment with clindamycin* plus quinine or atovaquone* plus azithromycin* are the options. The Medical Letter notes that exchange transfusion has been used in severely ill patients with high parasitemias. See recommendations in The Medical Letter for complete information.

* These drugs are approved by the FDA, but considered investigational for this purpose.

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