611
STATE-OF-THE-ART CLINICAL ARTICLE
Babesiosis
Maria R. Boustani and Jeffrey A. Gelfand
Babesia species are tick-borne, intraerythrocytic protozoa;
infection due to these organisms mimics malaria, causing he-
molysis, fever, anorexia, and hemoglobinuria. Babesia species
are well-known pathogens in animals, and over the past three
decades they have been recognized as occasional pathogens in
humans.
History
The first reported epidemic of babesiosis probably occurred
in biblical times and is referred to as the plague or divine
murrain that infected the cattle of the Pharaoh Ramses II (Exo-
dus 9:3). In 1888, Babes [1] described intraerythrocytic "bacte-
ria" as responsible for the deaths of 30,000-50,000 head of
Romanian cattle with febrile hemoglobinuria. In 1893 Smith
and Kilborne [2] recognized Babesia as a protozoan transmitted
by a blood-sucking tick, which was responsible for Texas cattle
fever. The first human case of babesiosis was reported in 1957
in a 33-year-old asplenic farmer from Yugoslavia [3]. Most
subsequent cases from Europe involved individuals who were
asplenic. In 1969, the first case of babesiosis in a patient with
an intact spleen was reported from Nantucket Island, Massa-
chusetts [4]. The organism involved, Babesia microti, caused
a disease that was milder than its European equivalent.
The Pathogen and Its Life Cycle
In nature, Babesia are probably the most frequent mamma-
lian intraerythrocytic parasites, with the exception of trypano-
somes. There are about 99 species of Babesia; these organisms
have a wide geographical range, and the range of ticks and
animals upon which the vectors feed is equally wide. Babesia
species are not as host specific as previously thought; however,
in general B. bovis, B. bigemina, B. divergens, and B. major
infect cattle; B. equi, horses; B. canis, dogs; B. felis, cats; and
B. microti, rodents. In the United States, B. microti-and more
recently WA-I, a strain isolated in Washington State-have
Received 27 December 1995.
Reprints or correspondence: Dr. Jeffrey A. Gelfand, New England Medical
Center, 750 Washington Street, Box 480, Boston, Massachusetts 02111.
Clinical Infectious Diseases 1996; 22:611-5
© 1996 by The University of Chicago. All rights reserved.
1058-4838/96/2204-0001$02.00
From the Department of Medicine, Tupper Research Institute, Tufts
University School ofMedicine; and the New England Medical Center,
Boston, Massachusetts
been identified as causing disease in humans, while in Europe
B. bovis and B. bigemina, the cattle strains, are implicated.
In the host, intraerythrocytic Babesia species vary in size
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from 1 to 5 /km in length and are oval, round, or pear-shaped.
The epidemiology of human babesiosis in the northeastern
United States has been thoroughly investigated because the
organisms are transmitted by the same vector, the tick Ixodes
dammini (also known as Ixodes scapularis) that transmits the
agent of Lyme disease, Borrelia burgdorferi. Little is known
about the transmission of babesiosis and its epidemiology in
other parts of the United States.
The family Babesiidae is characterized as consisting of non-
pigmented intraerythrocytic parasites that reproduce within
erythrocytes by asynchronous, asexual budding into two or four
daughter cells. The parasites are usually transmitted by hard-
bodied ticks of the Ixodes genus as well as other genera of
ticks including Boophilus, Dermacentor, Haemaphysalis, and
Rhipicephalus. In the northeastern United States, B. microti is
transmitted by 1. dammini, whereas in the United Kingdom,
the organism is transmitted by Ixodes trianguliceps. Ixodes
ricinus transmits bovine babesiosis in Europe. The vector re-
sponsible for the transmission of WA-I has not yet been de-
fined, but Ixodes pacificus is the most likely candidate.
The life cycle of 1. dammini spans ,...,2 years (figure 1). It
begins in the spring when the egg hatches, yielding the larval
form. Mainly during August and September, the larva feeds
on a variety of hosts, which acquire babesial infection. The
most common host (accounting for 90% of such animals on
Nantucket Island) is the white-footed mouse, Peromyscus leu-
copus. Other hosts include chipmunks, jumping mice, voles,
shrews, rabbits, and deer. In areas where transmission of Babe-
sia species is intense, ,..., 80% of the mice have been found
to be infected during late summer. In the tick, transstadial
transmission occurs: i.e., Babesia is transmitted from the larval
phase of the tick to the nymphal phase. The adult tick is more
host specific, preferring the white-tailed deer Odocoileus vir-
ginianus. The life cycle of the tick is then completed with the
deposition of eggs and the death of the tick.
Disease is transmitted to humans mostly by the nymph and
occasionally by the adult tick. The developmental stage of the
nymph occurs between May and July. The nymph measures
1-2 mm in length and is tan in color; thus, it can easily be
missed. The adult tick is larger and can be more easily seen
and removed.
612
Babesia ',/. .--.flI3~
Asexual ~
life cycle
in tick 'f
. '.:: Gut cell
~
(10 ·16 Hours)
division
Salivary glands
Tick
, t .,
life cycle
~j
Hosts
for
r
_ Wlll8-looted
tick moose'
Babesia
life cycle ~v Erythrocytic
cycle
in host ~~
Epidemiology
Human babesiosis continues to be rare in Europe. Eighty-
four percent of the 19 patients described were asp1enic and
lived in areas where cattle were numerous. Although there is
no national surveillance system for babesiosis in the United
States, hundreds of cases have been reported.
I. dammini started infesting the New England coast in the
early 1960s; its range appears to be increasing to include
densely populated areas in the northeastern United States, from
Massachusetts to Maryland and west to Wisconsin and Minne-
sota. The presence of 1. dammini seems to depend upon the
presence of white-tailed deer. Restocking of deer populations
and curtailment of hunting have increased deer herds substan-
tially. The clustering of most babesiosis cases in the Northeast
is thought to be secondary to the geographic proximity of
1. dammini and its different hosts. Cases have been reported
mostly in the coastal areas and islands of Massachusetts, Rhode
Island, and New York; however, cases have also been reported
in Connecticut, Maryland, Virginia, California, Wisconsin,
Minnesota, Georgia, and Washington State as well as in Mexico
[5].
The majority of infections with B. microti are asymptomatic.
Immunofluorescent antibody assays of sera collected from ran-
domly chosen college students in Connecticut have shown that
the percentage of persons with antibodies to the organism has
increased over the past 30 years and has remained constant
over the past 5 years. A serosurvey in Block Island, Rhode
Island, where babesiosis is endemic, showed that 9% of the
population (12% of children and 8% of adults) was seroposi-
tive, while in Connecticut 21% of the population (16% of
children and 22% of adults) was seropositive [6]. This study
Boustani and Gelfand em 1996;22 (April)
.-J
~
(9-10 months)
(2 years)
Figure 1. The life cycle of Ba-
besia microti.
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WhltHalled
de.
13~ 6~
demonstrated that babesial infection is as prevalent among chil-
dren as among adults and may cause an acute illness with fever,
chills, fatigue, diaphoresis, myalgia, arthralgia, or evidence of
hemolysis. The intensity of the disease appears to be greater
in adults older than 40 years.
An epidemiological survey of 136 cases in the state of New
York, where the largest number of cases has been reported,
showed advanced age to be the most important risk factor,
followed by absence of a spleen and immunodeficiency. The
incidence of babesiosis was higher among men, most likely
because of increased exposure to tick vectors through voca-
tional activities. Twenty-three percent ofthe patients with babe-
siosis had concurrent Lyme disease [7].
Pathogenesis and Clinical Presentation
The presentation of babesiosis is different in Europe and
North America. The parasites implicated in the European cases
have been either B. bovis or B. divergens and, in one case,
B. microti. Eighty-four percent of the European patients were
asplenic and presented with a fulminant febrile illness 1-3
weeks after receiving a tick bite. The disease was characterized
by hemoglobinuria, hemolysis, jaundice, chills, sweats, myal-
gia, pulmonary edema, and renal insufficiency. Coma and death
occurred in more than one-half ofthe cases. Subclinical babesi-
osis in patients with intact spleens has been reported in Europe
but is rare.
The majority of cases of babesiosis in the United States are
caused by the rodent strain B. microti. In contrast with the
European cases, most of the infections have been subclinical
and have involved patients with intact spleens. In general, pa-
CID 1996;22 (April) Babesiosis 613

cytosis and stomatocytosis. The absence of a spleen or the use

of corticosteroids may worsen the course of the disease and
prolong parasitemia.
Loss of membrane deformability has also been reported in
RBCs infected with B. bovis, resulting in an increase in mem-
brane lipid peroxidation [8]. This lipid peroxidation is believed
to promote the adherence of the erythrocytes to the endothelium
and cause microvascular stasis; in addition, erythrocyte survival
is shortened.

Diagnosis

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Babesiosis should be suspected in a patient with an unex-
plained febrile illness who has lived or traveled in a region
where the infection is endemic, especially when there is a
history of a tick bite during the months of June and July.
B. microti can be recognized in a Giemsa-stained blood
smear by the presence of intraeythrocytic ring forms (figure
Figure 2. Chest radiograph of an elderly patient with babesiosis
3). Early in the infection, the organism measures 0.9-2 us».
who developed adult respiratory distress syndrome shows an atypical
pattern due to severe bullous chronic obstructive pulmonary disease. With the onset of reproduction, the organism enlarges, and a
The atypical pattern developed during the course of treatment for blue-staining cytoplasm with a prominent red-staining nucleus
babesiosis with high-grade parasitemia. will appear. An unstained vacuole may be present. A few fea-
tures distinguish Babesia from Plasmodium, the agent responsi-
ble for malaria, including formation of tetrads (also known as
tients do not recall receiving a tick bite. After an incubation a "Maltese cross"), absence of pigment granules in infected
period of 1-4 weeks following the bite (or 6-9 weeks follow- RBCs, and the presence of extracellular merozoites.
ing transmission by blood transfusion), symptoms and signs Inspection of a peripheral blood smear could yield false-
gradually appear. The symptoms are nonspecific and include negative results when the level of parasitemia is low. The
fatigue, anorexia, myalgia, nausea, headache, sweating, rigors, indirect immunofluorescent assay (IFA) is antigen specific for
abdominal pain, emotional lability, depression, and dark urine. B. microti. A titer of ~ 1:64 is considered indicative of seropos-
Physical examination may show fever (which could be sus- itivity, and a titer of ~ 1:256 is diagnostic of acute infection.
tained or intermittent), mild hepatomegaly, petechiae, and ec- However, IFA remains of limited utility in clearly differentiat-
chymosis. Rash similar to that of erythema chronicum migrans
has been described and is probably caused by intercurrent Lyme
disease.
The laboratory findings may include a decreased hematocrit
and platelet count, with a normal or decreased WBC count
and elevated levels of lactate dehydrogenase, bilirubin, and
transaminases. Urinalysis reveals proteinuria and hemoglobin-
uria.
The level of parasitemia does not necessarily correlate with
the severity of symptoms and may persist for weeks to months;
it usually ranges between 1% and 10% but has been reported
to be < 1% and >85% in some patients on presentation.
Babesiosis can be severe, but it is rarely fatal. The clinical
course may be complicated by pulmonary edema. We have
noted that pulmonary edema occurs as the parasite count drops
in patients who have also been previously exposed to Lyme
disease (figure 2). Figure 3. Giemsa stain of human erythrocytes heavily infected with
B. microti reduces the deformability of the RBC it infects, Babesia microti (original magnification, xt ,250). Note the absence
of the brownish pigment deposits (hemozoin) commonly seen in Plas-
which would presumably facilitate the removal of infected
modium falciparum infection, although both P. falciparum and
RBCs by an intact spleen. Electron microscopic examination B. microti have ring forms. The larger ring forms of B. microti may
reveals extensive damage to the RBC membrane, including have a pale area, distinguishing the two organisms. The tetrads ("Mal-
protrusions, inclusions, perforations in addition to acantho- tese cross' ') of merozoites are characteristic of B. microti.
614 Boustani and Gelfand
ing between patients who have been exposed and those who
are actively infected; an alternative method in this case is the
detection of B. microti DNA by means of PCR.
B. microti may be differentiated from other Babesia isolates
either by intraperitoneal inoculation of infected blood into
golden hamsters (a time-consuming procedure that may require
1- 2 weeks) or by use of a ribosomal DNA probe.
Rapid diagnosis of B. divergens infection is crucial given
the fulminant course of the disease. Serological assays and
gerbil inoculation are used, usually retrospectively, to confirm
rather than establish the diagnosis because ofthe delay involved
(i.e., 1 week for seroconversion and 3-6 days for growth of
the parasite in the animal). Therefore, rapid diagnosis in such
instances will rely on the inspection of a blood smear for
Babesia organisms in RBCs.
Treatment
Chemotherapy for B. microti infection, which consists of a
combination of clindamycin and oral quinine, is reserved for
patients who have been splenectomized or who are immuno-
suppressed, elderly, or significantly symptomatic. The dosage
of clindamycin for adults is 1.2 g b.i.d, (given parenterally) or
600 mg t.i.d, (given orally) for 7 days; for children, three oral
doses of clindamycin (20-40 mg/[kg· dD should be given for
7 days. The dosage of quinine for adults is 650 mg t.i.d. (given
orally) for 7 days or 25 mg/(kg· d) given in three doses for 7
days. Pentamidine has proved to be effective in experimentally
infected hamsters; its efficacy in humans remains to be estab-
lished. Exchange transfusion is reserved for patients who are
extremely ill, with a high level of parasitemia (> 10%) and
hemolysis.
In animals, the antitrypanosomal drug diminazene aceturate
is effective against B. microti infections; its utility in humans
is uncertain.
Exchange transfusion (2-3 blood volumes) in combination
with c1indamycin and quinine therapy has proved effective in
the treatment ofthree cases of B. divergens infection. Treatment
should be started as soon as this disease is diagnosed because
the rapidly increasing parasitemia will lead to massive intravas-
cular hemolysis and renal failure.
Prevention
Prevention ofbabesiosis in asplenic or immunocompromised
patients is achieved by avoidance of regions of endemicity
during the months of May to September. Appropriate clothing
consists of long pants tucked under socks, which can protect
ern 1996;22 (April)
from tick bites and light-colored clothing that may enable early
recognition of the tick. Use of tick repellent-such as diethyl-
toluamide and dimethyl phthalate-on skin or clothes is rec-
ommended. Daily examination and removal of ticks with for-
ceps are crucial, since B. microti and B. burgdorferi require
attachment for> 24 hours before transmission occurs. In addi-
tion, pets must be carefully inspected for ticks.
In areas where babesiosis is endemic, blood donor screening
for B. microti by means of PCR would be ideal; in the interim,
blood donors who have had a febrile illness within 2 months
of donation (between the beginning of May and the end of
September) or donors with a history of a tick bite should be
rejected.
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References
1. Babes V. Sur l'hemoglobinurie bacterienne boeuf. Compt Rend Acad Sci
1888; 107:692-4.
2. Smith T, Ki1borne FL. Investigation into the nature, causation, and preven-
tion of southern cattle fever. US Dept Agr Bur Anim Indust Bull
1893; 1:1-301.
3. Skrabalo Z, Deanovi Z. Piroplasmosis in man: report on a case. Doc Med
Geogr Trop 1957;9:11-6.
4. Western KA, Benson GD, Gleason NN, et al. Babesiosis in a Massachusetts
resident. N Engl J Med 1970;283:854-6.
5. Dammin GJ, Spielman A, Benach JL, et al. The rising incidence of clinical
Babesiamicroti infection. Hum Patholl981; 12:398-400.
6. Krause PJ, Telford SR III, Pollack RJ, et al. Babesiosis: an underdiagnosed
disease of children. Pediatrics 1992;89:1045-8.
7. Meldrum SC, Birkhead GS, White DJ, Benach JL, Morse DL. Human
babesiosis in New York State: an epidemiological description of 136
cases. Clin Infect Dis 1992; 15:1019-23.
8. Krogstad DJ, Sutera SP, Boylan CW, et al. Intraerythrocytic parasites and
red cell deformability: Plasmodium berghei and Babesiamicroti. Blood
Cells 1991; 17:209-21.
Suggested Additional Readings
Boustani MR, Lepore TI, Gelfand JA, Lazarus DS. Acute respiratory failure
in patients treated for babesiosis. Am J Respir Crit Care Med
1994; 149:1689-91.
Francioli PB, Keithly JS, Jones TC, Brandstetter RD, Wolf DJ. Response of
babesiosis to pentamidine therapy. Ann Intern Med 1981;94:326-30.
Gelfand JA. Babesia. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell,
Douglas and Bennett's principles and practice of infectious diseases. 4th ed.
New York: Churchill Livingstone, 1995:2497-500.
Krause PJ, Telford SR III, Ryan R, et al. Diagnosis of babesiosis: evaluation
of a serologic test for the detection of Babesia microti antibody. J Infect
Dis 1994; 169:923-6.
Persing DH, Herwaldt BL, Glaser C, et al. Infection with a babesia-like organ-
ism in northern California. N Engl J Med 1995;332:298-303.
Rowin KS, Tanowitz HB, Wittner M. Therapy of experimental babesiosis.
Ann Intern Med 1982;97:556-8.
Spielman A. The emergence of Lyme disease and human babesiosis in a
changing environment. Ann NY Acad Sci 1994;740:146-56.
 615

OFFICE OF CONTINUING MEDICAL EDUCATION

UCLA SCHOOL OF MEDICINE
This test affords you the opportunity to assess your knowl- B. cause fever, anemia, chills, and fatigue.
edge and understanding of the material presented in the preced- C. be self-limited.
ing clinical article "Babesiosis," by Maria R. Boustani and D. all of the above.
Jeffrey A. Gelfand, and to earn continuing medical education
5. Which of the following are risk factors for developing
(CME) credit.
clinical babesiosis?
The Office of Continuing Medical Education, UCLA School
of Medicine, is accredited by the Accreditation Council for A. Immunosuppression.
Continuing Medical Education to sponsor continuing medical B. Absence of a spleen.
education for physicians. The Office of Continuing Medical C. Old age.

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Education, UCLA School ofMedicine, certifies that this contin-
uing medical education activity meets the criteria for 1 credit
hour in Category I of the Physician's Recognition Award of
the American Medical Association and the California Medical
Association Certificate in Continuing Medical Education.
To earn credit, read the State-of-the-Art Clinical Article care-
fully and answer the following questions. Mark your answer
by circling the correct responses on the answer card (usually
found toward the front of the issue) and mail after affixing first
class postage. To earn credit, a minimum score of 80% must
be obtained.
Certificates of CME credit will be awarded on a per volume
(biannual) basis. Each answer card must be submitted within
3 months of the date of issue.
This program is made possible by an educational grant from
Roche Laboratories.
1. In humans, Babesia invades which of the following?
A. The kidney.
B. The lung.
C. Erythrocytes.
D. All of the above.
2. The tick Ixodes dammini may transmit which ofthe follow-
ing?
A. Babesia microti.
B. Borrelia burgdorferi, the agent responsible for Lyme
disease.
C. None of the above.
D. Both of the above.
3. The clinical course of babesiosis is typically
A. more fulminant in Europe.
B. confined to the northeast coastal region of the United
States.
C. only apparent in individuals 60 years of age or older.
D. all of the above.
4. Babesiosis in North America may
A. be asymptomatic.
D. All of the above.
6. Diagnosis of babesiosis may be made by
A. inspection of a blood smear.
B. inoculation of golden hamsters.
C. indirect immunofluorescent antibody assay.
D. all of the above.
7. A 50-year-old man is found to have intraerythrocytic inclu-
sions consistent with babesia infection on inspection of a
blood smear. The blood was drawn as part of a routine
physical examination. He is asymptomatic but admits to
receiving a tick bite 5 weeks earlier during a weekend on
Nantucket Island. What is the recommended treatment?
A. Intravenous clindamycin and oral quinine.
B. Oral quinine and oral clindamycin.
C. Exchange transfusion.
D. None of the above.
8. Babesiosis in Europe
A. may be transmitted by B. microti.
B. causes hemolysis and renal insufficiency.
C. is rarely fatal.
D. all of the above.
9. You are asked by your patient about prevention of babesio-
sis. What do you recommend?
A. Patients who are at high risk of developing babesiosis
should avoid areas of endemicity.
B. Patients should not receive premedication before trav-
eling to an area where the infection is endemic.
C. Wearing protective clothing and inspecting daily for
ticks.
D. All of the above.
10. Babesia may be transmitted to humans by which of the
following routes?
A. The bite of any tick.
B. A blood transfusion.
C. The bite of a white-footed mouse.
D. All of the above.