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. Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014 History From the Department of Medicine, Tupper Research Institute, Tufts University School ofMedicine; and the New England Medical Center, Boston, Massachusetts 612 em 1996;22 Boustani and Gelfand ',/. 'f (April) .--.flI3~ Asexual ~ Babesia life cycle in tick . '.:: Gut cell .-J ~ division (10 ·16 Hours) ~ Salivary glands (9-10 months) (2 years) Tick life cycle Hosts for tick Wlll8-looted ~j moose' ~v Erythrocytic cycle t ., besia microti. WhltHalled de. 13~ 6~ ~~ 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- Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014 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. Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014 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. Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014 Treatment ern 615 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. Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014 This test affords you the opportunity to assess your knowledge and understanding of the material presented in the preceding clinical article "Babesiosis," by Maria R. Boustani and Jeffrey A. Gelfand, and to earn continuing medical education (CME) credit. The Office of Continuing Medical Education, UCLA School of Medicine, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. The Office of Continuing Medical Education, UCLA School ofMedicine, certifies that this continuing 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 carefully 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.
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