Document 6478933

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 hemolysis, 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.
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 (Exodus 9:3). In 1888, Babes [1] described intraerythrocytic "bacteria" 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, Massachusetts [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 mammalian intraerythrocytic parasites, with the exception of trypanosomes. 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
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
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 nonpigmented intraerythrocytic parasites that reproduce within
erythrocytes by asynchronous, asexual budding into two or four
daughter cells. The parasites are usually transmitted by hardbodied 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 responsible for the transmission of WA-I has not yet been defined, 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 leucopus. Other hosts include chipmunks, jumping mice, voles,
shrews, rabbits, and deer. In areas where transmission of Babesia 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 virginianus. 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.
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History
From the Department of Medicine, Tupper Research Institute, Tufts
University School ofMedicine; and the New England Medical Center,
Boston, Massachusetts
612
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Boustani and Gelfand
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Epidemiology
Human babesiosis continues to be rare in Europe. Eightyfour 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 Minnesota. 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 substantially. 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 randomly 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 seropositive, while in Connecticut 21% of the population (16% of
children and 22% of adults) was seropositive [6]. This study
demonstrated that babesial infection is as prevalent among children 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 vocational activities. Twenty-three percent ofthe patients with babesiosis 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, myalgia, pulmonary edema, and renal insufficiency. Coma and death
occurred in more than one-half ofthe cases. Subclinical babesiosis 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-
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Babesia
life cycle
in host
,
r
_
Figure 1. The life cycle of Ba-
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 membrane 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
tients do not recall receiving a tick bite. After an incubation
period of 1-4 weeks following the bite (or 6-9 weeks following transmission by blood transfusion), symptoms and signs
gradually appear. The symptoms are nonspecific and include
fatigue, anorexia, myalgia, nausea, headache, sweating, rigors,
abdominal pain, emotional lability, depression, and dark urine.
Physical examination may show fever (which could be sustained or intermittent), mild hepatomegaly, petechiae, and ecchymosis. 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 hemoglobinuria.
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).
B. microti reduces the deformability of the RBC it infects,
which would presumably facilitate the removal of infected
RBCs by an intact spleen. Electron microscopic examination
reveals extensive damage to the RBC membrane, including
protrusions, inclusions, perforations in addition to acantho-
Figure 3. Giemsa stain of human erythrocytes heavily infected with
Babesia microti (original magnification, xt ,250). Note the absence
of the brownish pigment deposits (hemozoin) commonly seen in Plasmodium falciparum infection, although both P. falciparum and
B. microti have ring forms. The larger ring forms of B. microti may
have a pale area, distinguishing the two organisms. The tetrads ("Maltese cross' ') of merozoites are characteristic of B. microti.
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Figure 2. Chest radiograph of an elderly patient with babesiosis
who developed adult respiratory distress syndrome shows an atypical
pattern due to severe bullous chronic obstructive pulmonary disease.
The atypical pattern developed during the course of treatment for
babesiosis with high-grade parasitemia.
Babesiosis should be suspected in a patient with an unexplained 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
3). Early in the infection, the organism measures 0.9-2 us».
With the onset of reproduction, the organism enlarges, and a
blue-staining cytoplasm with a prominent red-staining nucleus
will appear. An unstained vacuole may be present. A few features distinguish Babesia from Plasmodium, the agent responsible for malaria, including formation of tetrads (also known as
a "Maltese cross"), absence of pigment granules in infected
RBCs, and the presence of extracellular merozoites.
Inspection of a peripheral blood smear could yield falsenegative results when the level of parasitemia is low. The
indirect immunofluorescent assay (IFA) is antigen specific for
B. microti. A titer of ~ 1:64 is considered indicative of seropositivity, and a titer of ~ 1:256 is diagnostic of acute infection.
However, IFA remains of limited utility in clearly differentiat-
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.
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 immunosuppressed, 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 established. 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 intravascular 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
1996;22 (April)
from tick bites and light-colored clothing that may enable early
recognition of the tick. Use of tick repellent-such as diethyltoluamide and dimethyl phthalate-on skin or clothes is recommended. Daily examination and removal of ticks with forceps are crucial, since B. microti and B. burgdorferi require
attachment for> 24 hours before transmission occurs. In addition, 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.
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 prevention 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 organism 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.
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Treatment
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OFFICE OF CONTINUING MEDICAL EDUCATION
UCLA SCHOOL OF MEDICINE
B. cause fever, anemia, chills, and fatigue.
C. be self-limited.
D. all of the above.
5. Which of the following are risk factors for developing
clinical babesiosis?
A. Immunosuppression.
B. Absence of a spleen.
C. Old age.
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 inclusions 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.
1. In humans, Babesia invades which of the following?
8. Babesiosis in Europe
A. The kidney.
A. may be transmitted by B. microti.
B. The lung.
B. causes hemolysis and renal insufficiency.
C. Erythrocytes.
C. is rarely fatal.
D. All of the above.
2. The tick Ixodes dammini may transmit which ofthe following?
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.
D. all of the above.
9. You are asked by your patient about prevention of babesiosis. 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 traveling 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?
C. only apparent in individuals 60 years of age or older.
A. The bite of any tick.
D. all of the above.
B. A blood transfusion.
4. Babesiosis in North America may
A. be asymptomatic.
C. The bite of a white-footed mouse.
D. All of the above.
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