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Babesiosis
Babesiosis Peter J. Krause, MD Babesiosis is a zoonotic disease caused by an intraerythrocytic protozoan that is transmitted by Ixodes ticks. Babesiosis has been recognized as an emerging endemic disease in the northeastern and northern midwestern United States, with sporadic cases reported in the Far West and in Europe, Africa, and Asia. Although children are infected as frequently as are adults and may have serious episodes of disease, cases are reported more commonly in adults. The clinical spectrum of babesiosis ranges from asymptomatic infection to death. Typical clinical symptoms include fever, chills, sweats, headache, and fatigue. Patients at increased risk for severe disease include those who lack a spleen, are infected with human immunodeficiency virus, are older than 50 years, or are coinfected with the agents of Lyme disease or ehrlichiosis. Definitive laboratory diagnosis can be made by direct identification of the causative agent in Giemsa-stained peripheral blood smears and by serological evaluation. The combination of clindamycin and quinine is the current treatment of choice for babesiosis. Copyright 娀 2000 by W.B. Saunders Company
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abesiosis (piroplasmosis) is a zoonotic disease caused by an intraerythrocytic protozoan that is transmitted by Ixodes ticks. The clinical spectrum of babesiosis ranges from asymptomatic infection to death. Parasite replication often produces only mild anemia with few associated symptoms, but it also may cause severe anemia with numerous clinical manifestations, including high fever, chills, sweats, hypotension, pulmonary edema, disseminated intravascular coagulation, hemoglobinuria, and renal failure. The first historical record of babesial infection may have been the biblical reference to a plague of murrain (hemoglobinuria) among cattle and other domestic animals (Exodus 9:3). The parasite was first described in 1888 in cattle by the Hungarian microbiologist Babes.1 Five years later, Smith and Kilbourne2 identified ticks as the source of Texas cattle fever caused by Babesia bigemina, and in so doing established for the first time that pathogens could be transmitted by arthropods. Since then, approximately 100 species of Babesia that infect a wide variety of wild and domestic animals throughout the world, including mice, rodents, deer, dogs, and cattle, have been described.3 The first human case of babesiosis was reported in 1957 in a 33-year-old asplenic cattle farmer from Yugoslavia.4 In 1969, a case of babesiosis in a patient with an intact spleen was reported from Nantucket Island, Massachusetts.5 Subsequently,
From the Department of Pediatrics, University of Connecticut School of Medicine, Farmington, and the Section of Pediatric Infectious Diseases, Connecticut Children’s Medical Center, Hartford, CT. Supported by grant AI 42402 from the National Institutes of Health. Address correspondence to Peter J. Krause, MD, Director, Pediatric Infectious Diseases, Connecticut Children’s Medical Center, 282 Washington St, Hartford, CT 06106. Copyright 娀 2000 by W.B. Saunders Company 1045-1870/00/1103-0007$10.00/0 doi:10.1053/pi.2000.6229
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babesiosis has been recognized as an emerging endemic disease in the northeastern and northern midwestern United States, with sporadic cases reported in the Far West and in Europe, Africa, and Asia.6-19
Epidemiology Geographic Range Babesia species have a wide host and geographic range. In general, B bovis, B bigemina, B divergens, and B major infect cattle; B equi infects horses; B canis infects dogs; B felis infects cats; and B microti infects rodents.3 Four species are known to cause disease in humans. B microti, WA-1 (a strain originally isolated from a resident of Washington State and very closely related to B gibsoni), and MO 1 (isolated from a resident of Missouri and closely related to B divergens) are the causative agents in the United States, whereas B divergens and B bovis are found in Europe. In the United States, most human cases have been reported from the coastal areas of southern New England and eastern Long Island, but others have been reported in California, Minnesota, Missouri, New Jersey, Wisconsin, and Washington State.5-16 The number of cases of babesiosis appears to be increasing in endemic areas in the northeastern United States.6,8-10 In one study of a highly endemic area, approximately 9 percent of the population had evidence of previous B microti infection, compared with 11 percent with previous Lyme disease (Fig 1).10 The public health significance of zoonotic babesiosis may be greater than previously estimated.
Babesiosis in Children B microti is transmitted by the same Ixodes tick that transmits Borrelia burgdorferi, the causative agent of Lyme disease. Children have a higher incidence of Lyme disease than does any other age group. Despite such evidence of intense exposure to these ticks,
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Figure 1. Age related distribution of babesiosis and Lyme borreliosis in an endemic area. Age distribution of residents on Block Island, Rhode Island whose sera reacted with Babesia microti antigen (dark bars) and those whose sera reacted with Borrelia burgdorferi antigen (stippled bars). There was no significant difference in the percentage of children (n ⫽ 52) and adults (n ⫽ 522) whose sera reacted to B microti antigen and B burgdorferi antigen. (Reproduced by permission of PEDIATRICS, Vol. 89 Pages 1045-1048 Copyright 1992.10) only five children have been described with babesiosis, compared with hundreds of reported cases in adults.10,20-22 To resolve this apparent paradox, we conducted a prospective serosurvey of B microti antibody in residents of Block Island, Rhode Island (a
site in which the infection is endemic) and reviewed data from a large-scale retrospective Lyme disease and babesiosis serosurvey in Connecticut.10 The percentages of children seropositive to B microti on Block Island and in Connecticut (12 and 16 percent, respectively) were similar to those of adults (8 and 22 percent, respectively) (Fig 1). We concluded that children in both areas were exposed to babesial infection about as frequently as were adults. Interestingly, we found that of those seropositive for B microti, children reported an illness compatible with babesiosis at a greater rate than did adults, although the numbers were insufficient to predict rigorous correlation of disease severity with age. Despite such data and published reports that babesiosis in children may result in serious episodes of disease, it is unclear whether the relatively small numbers of reported babesial cases in children is caused by milder illness, an increased familiarity of babesiosis on the part of physicians caring for adults, or a more aggressive workup of fever in adults, including evaluation for babesiosis.10
Transmission and Immunity Babesial parasites usually are transmitted by hard-bodied ticks of the Ixodes genus. In the northeastern United States, B microti is transmitted by I dammini (also known as I scapularis).8 The precise vector for WA-1 has not been identified, but it is
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Figure 2. Life cycle of I dammini. (Reprinted, with permission, from the Annual Review of Entomology, Volume 30 娀1985 by Annual Reviews www. AnnualReviews.org.8)
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suspected to be I pacificus.12 Bovine babesiosis is transmitted by I ricinus in Europe.17 The life cycle of I dammini spans 2 years and has 3 active stages: larva, nymph, and adult (Fig 2). Each stage takes a blood meal from a vertebrate host to mature to the next stage. Disease usually is transmitted to humans by the nymph between May and September, but occasionally it is transmitted by the adult tick outside the usual transmission season. The major reservoir host of B microti in the northeastern United States is the white-footed mouse (Peromyscus leucopus). The white-tailed deer (Odocoileus virginianus) is the principal host of the adult tick. Rarely, babesiosis is acquired through blood transfusion.23-25 Whole blood, frozen erythrocytes, and platelets have been implicated. Transplacental-perinatal transmission of babesiosis also has been described.20 Immunity after babesial infection is incomplete. Low-level parasitemia may exist for months to years in cattle and as long as 26 months in humans after recovery from the initial illness.26 The spleen plays a critical role in protection against Babesia species. Most fatal cases of babesiosis in humans have occurred in splenectomized individuals, although asplenia does not always result in death or even severe illness.27 The spleen is thought to protect against babesial infection by removing and phagocytizing parasites from infected erythrocytes and by the production of antibabesial antibody. Other host defense mechanisms that may help limit babesial infection include T and B lymphocytes, antibody, complement, macrophages and macrophage products such as tumor necrosis factor (TNF), and polymorphonuclear leukocytes.15
Symptomatology Nature, Duration, and Course In the natural reservoir (white-footed mouse), B microti may be detected as early as 1 to 2 days after infective ticks have completed feeding. The time from infection until onset of symptoms (incubation period) is estimated to be 1 to 6 weeks for tick-borne transmission and 6 to 9 weeks for transfusion cases.7,23 Often, the patient has no recollection of a tick bite because the
unengorged I dammini nymph is only about 2 mm in length (Fig 3). The clinical severity of babesiosis includes subclinical infection, nonspecific flu-like illness, moderately severe malaria-like illness, and, in rare instances, fulminating disease resulting in death. Inapparent or mild infection is the most common form of the disease, as suggested by serosurvey data from endemic areas.7,9,10 Typical symptoms in moderate-to-severe infection include intermittent fever with a temperature as high as 40°C (104°F) and one or more of the following: chills, sweats, myalgia, arthralgia, nausea, and vomiting.7,28-30 Less commonly noted are emotional lability and depression, hyperesthesia, headache, sore throat, abdominal pain, conjunctival injection, photophobia, weight loss, and nonproductive cough. Unlike plasmodium merozoites, which are released from erythrocytes in synchrony, Babesia species reproduce by asynchronous, asexual budding. This asynchrony decreases the possibility of sudden extensive hemolysis and explains the lack of periodicity of symptoms that characterizes malaria. The findings on physical examination generally are minimal, often consisting only of fever. Mild splenomegaly, hepatomegaly, or both are noted occasionally.28-30 Slight pharyngeal erythema, jaundice, retinopathy with splinter hemorrhages, and retinal infarcts also have been reported. Unlike other tick-borne illnesses such as Lyme disease, Rocky Mountain spotted fever, or tularemia, rash seldom is noted. Patients with babesiosis have been reported with erythema chronicum migrans (ECM), but these patients most likely had concurrent Lyme disease. Several abnormal laboratory findings in patients with babesiosis reflect the invasion and subsequent lysis of erythrocytes by the parasite. Mild to moderately severe hemolytic anemia is common, with an elevated reticulocyte count.28 Elevated liver function tests occur in approximately one-half the patients. The leukocyte count is normal to slightly decreased, with a ‘‘left shift.’’ Atypical lymphocytes may be noted on manual differential blood smear examination. Thrombocytopenia is typical.28 The erythrocyte sedimentation rate is elevated. Proteinuria and elevated blood urea nitrogen (BUN) and creatinine levels also may be noted.
Figure 3. I dammini ticks (also known as I scapularis). From left to right, adult male, adult female, blood engorged female. A common pin is shown for size comparison.
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Babesiosis Table 1. Diversity and Duration of Disease in Symptomatic Subjects From Block Island and Connecticut Infected by the Agents of Lyme Disease (Borrelia) Alone, of Human Babesiosis (Babesia) Alone, and of Both Pathogens Detected Simultaneously
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ecchymoses, petechiae, congestive heart failure, pulmonary edema, renal failure, adult respiratory distress syndrome, and coma.27 The severity of human illness appears to correlate with age. Although babesial infection appears to be less severe in children than in adults, moderate-to-severe babesiosis may occur in children. Several cases of neonatal babesiosis have been described.20,22 One infant was severely ill, and the others were moderately ill with fever (temperature as high as 40°C) and irritability. Other findings included lethargy, tachypnea, pallor, poor feeding, jaundice, splenomegaly, and hepatomegaly. Common laboratory findings included anemia, thrombocytopenia, and increased levels of bilirubin and liver enzymes.
Complications Babesiosis usually lasts for a few weeks to several months, with prolonged recovery of up to 18 months. Parasitemia may continue even after the patient feels well. It has been found to persist in humans for as long as 17 months, and relapse of illness, as noted with malaria, has been noted 26 months after the initial episode (Fig 4).26 Patients with severe babesiosis may have a fatal outcome. In an epidemiological study of 136 cases of babesiosis from Long Island, New York, 7 patients (5 percent) died.11 The patients with fatal illness ranged in age from 60 to 82 years. Only one was known to be immunocompromised (cirrhosis). Although no reports of well-described long-term morbidity caused by babesiosis exist, anecdotal reports suggest that some patients have prolonged fatigue after acute illness.
Diagnosis Babesiosis should be suspected in any patient with an unexplained febrile illness who has recently lived or traveled to an endemic region during May through September, with or without
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Special Groups at Risk Patients at risk for severe disease include those who lack a spleen, are infected with HIV, are older than 50 years, or are coinfected with the agents of Lyme disease or ehrlichiosis.27,30-32 Coinfection with babesiosis in patients with Lyme disease is common in endemic areas of southern New England, occurring in approximately 10 to 15 percent of all Lyme disease cases.9,30 A recent study has shown that patients with coinfection of babesiosis and Lyme disease have more symptoms and are ill for a longer time than those with either infection alone (Table 1).30 Individuals with prior splenectomy generally have a severe form of B microti babesiosis that consists of fulminant illness lasting approximately a week and ending in death or a prolonged convalescence. Signs and symptoms include high fever, hemolytic anemia, hemoglobinemia and hemoglobinuria, jaundice,
Figure 4. Persistence of DNA amplifiable by polymerase chain reaction (PCR) in the blood of B microti–infected subjects who received specific antibabesial therapy as compared with subjects who received no such treatment. The 22 subjects treated with clindamycin and quinine had a shorter duration of parasitemia than did the 24 untreated subjects (P ⫽ .05 by the log-rank test). (Reprinted by permission of The New England Journal of Medicine. Krause PJ, Spielman A, Telford S, et al: Persistent parasitemia following acute babesiosis. N Engl J Med 339:160165, 1998.26 Copyright 娀1998 Massachusetts Medical Society. All rights reserved.)
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a history of tick bite. During the acute phase of babesiosis, definitive laboratory diagnosis can be made by direct identification of the causative agent in Giemsa-stained peripheral blood smears. The predominant forms in most blood smears are small (1.0-5.0 µm in length), round to oval ring-shaped intraerythrocytic structures that closely resemble those of Plasmodium species (Fig 5).15 Although uncommon, tetrad forms (Maltese-cross) are pathogenomonic of the disease, which together with the presence of extracellular merozoites and absence of pigment granules in infected erythrocytes distinguish them from Plasmodium. Multiple examination of both thick and thin smears is preferable because most documented cases of human babesiosis have had a low parasitemia. The level of parasitemia usually ranges between 1 and 10 percent in normal hosts and up to 85 percent in asplenic and other high-risk individuals. Specific diagnosis of babesiosis can be made by serological evaluation. Of the commonly used serologic tests, indirect immunofluorescent assay (IFA) is the most reliable.33-35 Patients with a babesial antibody titer of 1:32 or higher generally are considered to be seropositive, whereas those with a titer of 1:1,024 or greater usually are actively or recently infected. Cross-reactivity with other Babesia species and Plasmodium can occur. An IgM IFA test is available and suitable for routine clinical diagnosis of acute babesiosis.35 Thus, serology may quickly confirm a diagnosis of babesiosis when parasites are scarce or not detectable. In cases that are difficult to diagnose by smear or serology, detection of even mild parasitemia can be accomplished by inoculating the patient’s blood into a hamster.36 Parasitemia is amplified to detectable levels within the hamster from 2 to 4 weeks after inoculation. This method of confirmatory diagnosis requires a specialized laboratory. The polymerase chain reaction (PCR) should supplant the hamster inoculation test when laboratory proficiency and certification mechanisms are instituted.37,38 In experienced hands, PCR sensitively and specifically detects Babesia DNA within an afternoon.
Differential Diagnosis The clinical manifestations of malaria most closely resemble those of babesiosis, but malaria is less likely if the patient has not traveled recently to a malarious area. Babesial parasites can be distinguished readily from those of malaria on thin blood smear by an experienced microscopist. The initial clinical presentation of other tick-borne pathogens such as Lyme disease and ehrlichiosis may resemble that of babesiosis. Babesiosis is not associated with a rash, however, and other tick-borne pathogens seldom cause anemia.
Therapy Because of frequent misdiagnosis of babesiosis as P falciparum infection, chloroquine was commonly used in the very first babesiosis cases; however, it often fails to clear parasitemia and is not recommended for use in babesiosis. The combination of clindamycin and quinine is the current therapy of choice for babesiosis. This combination was used initially in the first reported case of babesiosis in a child, an 8-week-old who contracted babesiosis from a blood transfusion.24 Initially, she was thought to have malaria. Clindamycin (20 mg/kg/d) and quinine (25 mg/kg/d) were given after failure with chloroquine. Her favorable outcome suggested the prospective use of this combination in adults. Subsequently, numerous children and adults have been treated with clindamycin and quinine, with prompt clearing of parasitemia and resolution of clinical signs and symptoms.39 Treatment failures have been reported for this regimen, however, particularly in patients infected with human immunodeficiency virus (HIV). Preliminary results of a prospective, randomized treatment trial suggest that atovaquone (750 mg every 12 hours) and azithromycin (500 mg on day 1, then 250 mg/d thereafter) is as effective as clindamycin (600 mg every 8 hours) and quinine
Figure 5. Ring forms of B microti in human blood film (original magnification, ⫻1000).
Babesiosis (650 mg every 8 hours) for treatment of adults with babesiosis but is associated with fewer reported adverse events.40 Exchange blood transfusions have been used successfully in splenectomized patients with life-threatening babesiosis41 and can rapidly decrease parasitemia and remove toxic byproducts of babesial infections. Exchange transfusion should be used only in the most severe infections, such as in patients with a high parasitemia (more than 5 percent) and coma, hypotension, congestive heart failure, pulmonary edema, or renal failure. In combination with clindamycin and quinine, it is the treatment of choice for all cases of B divergens babesiosis. Quantitating parasitemia would seem to be critical in managing individuals with severe babesiosis, such as those with asplenia or HIV. Blood smears should be examined every 4 hours after administration of the first dose of clindamycin and quinine, and alternative therapy should be considered if parasitemia does not appear to decline appreciably within 24 hours.
Prevention Prevention of babesiosis can be accomplished by avoiding areas in May through September where ticks, deer, and mice are known to thrive. Especially important for those at increased risk in endemic areas, such as asplenic individuals, is avoidance of tall grass and brush where ticks may abound.8 Use of clothing that covers the lower part of the body and that is sprayed or impregnated with diethyltoluamide (DEET), dimethyl phthalate, or permethrin (Permanone) is recommended for those who travel in the foliage of endemic areas. A search for ticks on people and pets should be performed and the ticks removed as soon as possible. The latter is accomplished best by removal with tweezers by grasping the mouth parts without squeezing the body of the tick.42 Deer reduction might serve to diminish drastically human risk of tick-borne infection in a community. Deer were virtually eliminated on Great Island off Cape Cod, Massachusetts, and within 3 to 5 years the density of I dammini ticks decreased precipitously.43 Only one case of Lyme disease has been reported from that site since deer reduction. Host-seeking ticks may be killed by applications of acaricide to vegetation around yards or by targeted application using impregnated cotton, which mice carry back to their nests (Damminix). Prospective blood donors who reside in endemic areas and who have a history of fever within the preceding 1 to 2 months should be excluded from giving blood to prevent transfusionrelated cases. No vaccine has yet been developed against B microti or B gibsoni (WA1).
References 1. Babes V: Sur L’hemoglobinurie bacterienne boeuf. Compt Rend Acad Sci 107:692-694, 1888 2. Smith T, Kilbourne FL: Investigation into the nature, causation, and prevention of southern cattle fever. US Dept Agr Bur Anim Indust Bull 1:1-301, 1893 3. Levine ND: The Protozoan Phylum Apicomplexa, vol 2. Boca Raton, FL, CRC Press, 1988 4. Skrabalo A, Deanovic A: Piroplasmosis in man. Report on a case. Doc Med Geogr Trop 9:11-16, 1957
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5. Western KA, Benson GD, Gleason NN, et al: Babesiosis in a Massachusetts resident. N Engl J Med 283:854-856, 1970 6. Dammin GJ, Spielman A, Benach JL, et al: The rising incidence of clinical Babesia microti infection. Hum Pathol 12:398-400, 1981 7. Ruebush TK II, Juranek DD, Chisholm ES, et al: Human babesiosis on Nantucket Island: Evidence for self-limited and subclinical infections. N Engl J Med 297:825-827, 1977 8. Spielman A, Wilson ML, Levine JF, et al: Ecology of Ixodes damminiborne human babesiosis and Lyme disease. Ann Rev Entomol 30:439-460, 1985 9. Krause PJ, Telford SR, Ryan R, et al: Geographical and temporal distribution of babesial infection in Connecticut. J Clin Microbiol 29:1-4, 1991 10. Krause PJ, Telford SR, Pollack RJ, et al: Babesiosis: An underdiagnosed disease of children. Pediatrics 89:1045-1048, 1992 11. Meldrum SC, Birkhead GS, White DJ, et al: Human babesiosis in New York State: An epidemiological description of 136 cases. Clin Infect Dis 15:1019-1023, 1992 12. Persing DH, Herwaldt BL, Glaser C, et al: Infection with a Babesia-like organism in the western United States. N Engl J Med 332:298-303, 1995 13. Steketee RW, Eckman MR, Burgess EC, et al: Babesiosis in Wisconsin: A new focus of disease transmission. JAMA 253:26752678, 1985 14. Herwaldt BL, Persing DH, Precigout EA, et al: A fatal case of babesiosis in Missouri: Identification of another piroplasm that infects humans. Ann Intern Med 124:643-650, 1995 15. Krause PJ: Babesiosis, in Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases, vol 2 (ed 4). Philadelphia, PA, Saunders, 1998, pp 2432-2437 16. Eskow ES, Krause PJ, Spielman A, et al: Southern extension of the range of human babesiosis in the eastern United States. J Clin Microbiol 37:2051-2052, 1999 17. Garnham PCC: Human babesiosis: European aspects. Trans R Soc Trop Med Hyg 74:153-155, 1980 18. Bush JB, Isaacson M, Mohamed AS: Human babesiosis: A preliminary report of two suspect cases in southern Africa. S Afr Med J 78:699, 1990 (letter) 19. Hsu NHM, Cross JH: Serologic survey for human babesiosis on Taiwan. J Formos Med Assoc 76:950-954, 1977 20. Esernio-Jenssen D, Scimeca PG, Benach JL, et al: Transplacental/ perinatal babesiosis. J Pediatr 110:570-572, 1987 21. Mathewson HO, Anderson AE, Hazard JGW: Self-limited babesiosis in a splenectomized child. Pediatr Infect Dis 3:148-149, 1984 22. Scimeca PG, Weinblatt ME, Schonfeld G: Babesiosis in two infants from eastern Long Island, N.Y. Am J Dis Child 140:971, 1986 (letter) 23. Mintz ED, Anderson JF, Cable RG, et al: Transfusion-transmitted babesiosis: A case report from a new endemic area. Transfusion 31:365-368, 1991 24. Wittner M, Rowin KS, Tanowitz HB, et al: Successful chemotherapy of transfusion babesiosis. Ann Intern Med 96:601-604, 1982 25. Gerber MA, Shapiro ED, Krause PJ, et al: The risk of acquiring Lyme disease or babesiosis from a blood transfusion. J Infect Dis 170:231-234, 1994 26. Krause PJ, Spielman A, Telford S, et al: Persistent parasitemia following acute babesiosis. N Engl J Med 339:160-165, 1998 27. Rosner F, Zarrabi MH, Benach JL, et al: Babesiosis in splenectomized adults: Review of 22 reported cases. Am J Med 76:696-701, 1984 28. Sun T, Tenenbaum MJ, Greenspan J, et al: Morphologic and clinical observations in human infection with Babesia microti. J Infect Dis 148:239-248, 1983 29. Benach JL, Habicht GS: Clinical characteristics of human babesiosis. J Infect Dis 144:481, 1981
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30. Krause PJ, Telford S, Spielman A, et al: Concurrent Lyme disease and babesiosis: Evidence for increased severity and duration of illness. JAMA 275:1657-1660, 1996 31. Benezra D, Brown AE, Polsky B, et al: Babesiosis and infection with human immunodeficiency virus (HIV). Ann Intern Med 107:944, 1987 (letter) 32. Falagas ME, Klempner MS: Babesiosis in patients with AIDS: A chronic infection presenting as fever of unknown origin. Clin Infect Dis 22:809-812, 1996 33. Chisholm ES, Ruebush TK II, Sulzer AJ, et al: Babesia microti infection in man: Evaluation of an indirect immunofluorescent antibody test. Am J Trop Med Hyg 27:14-19, 1978 34. Krause PJ, Telford SR, Ryan R, et al: Diagnosis of babesiosis: Evaluation of a serologic test for the detection of Babesia microti antibody. J Infect Dis 169:923-926, 1994 35. Krause PJ, Ryan R, Telford S: Efficacy of an IgM serodiagnostic test for the rapid diagnosis of acute babesiosis. J Clin Microbiol 34:20142016, 1996 36. Etkind P, Piesman J, Ruebush TK: Methods for detecting Babesia microti infection in wild rodents. J Parasitol 66:107-110, 1980 37. Persing DH, Mathiesen D, Marshall WF, et al: Detection of Babesia
38.
39. 40.
41.
42. 43.
microti by polymerase chain reaction. J Clin Microbiol 30:2097-2103, 1992 Krause PJ, Telford S, Spielman A: Comparison of PCR with blood smear and small animal inoculation for diagnosis of Babesia microti parasitemia. J Clin Microbiol 34:2791-2794, 1996 Centers for Disease Control: Clindamycin and quinine treatment for Babesia microti infections. MMWR 32:65-72, 1983 Krause PJ, Telford SR, Spielman A, et al: Treatment of babesiosis: Comparison of atovaquone and azithromycin with clindamycin and quinine. Program and Abstracts of the 46th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Lake Buena Vista, FL, 1997, p 247 (abstr 430) Jacoby GA, Hunt JV, Kosinski KS, et al: Treatment of transfusiontransmitted babesiosis by exchange transfusion. N Engl J Med 303:1098-1100, 1980 Needham GR: Evaluation of five popular methods for tick removal. Pediatrics 75:997-1002, 1988 Wilson ML, Telford SR, Piesman J, et al: Reduced abundance of immature Ixodes dammini (Acari: Ixodidae) following elimination of deer. J Med Entomol 25:224-228, 1988
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abesiosis (piroplasmosis) is a zoonotic disease caused by an intraerythrocytic protozoan that is transmitted by Ixodes ticks. The clinical spectrum of babesiosis ranges from asymptomatic infection to death. Parasite replication often produces only mild anemia with few associated symptoms, but it also may cause severe anemia with numerous clinical manifestations, including high fever, chills, sweats, hypotension, pulmonary edema, disseminated intravascular coagulation, hemoglobinuria, and renal failure. The first historical record of babesial infection may have been the biblical reference to a plague of murrain (hemoglobinuria) among cattle and other domestic animals (Exodus 9:3). The parasite was first described in 1888 in cattle by the Hungarian microbiologist Babes.1 Five years later, Smith and Kilbourne2 identified ticks as the source of Texas cattle fever caused by Babesia bigemina, and in so doing established for the first time that pathogens could be transmitted by arthropods. Since then, approximately 100 species of Babesia that infect a wide variety of wild and domestic animals throughout the world, including mice, rodents, deer, dogs, and cattle, have been described.3 The first human case of babesiosis was reported in 1957 in a 33-year-old asplenic cattle farmer from Yugoslavia.4 In 1969, a case of babesiosis in a patient with an intact spleen was reported from Nantucket Island, Massachusetts.5 Subsequently,
From the Department of Pediatrics, University of Connecticut School of Medicine, Farmington, and the Section of Pediatric Infectious Diseases, Connecticut Children’s Medical Center, Hartford, CT. Supported by grant AI 42402 from the National Institutes of Health. Address correspondence to Peter J. Krause, MD, Director, Pediatric Infectious Diseases, Connecticut Children’s Medical Center, 282 Washington St, Hartford, CT 06106. Copyright 娀 2000 by W.B. Saunders Company 1045-1870/00/1103-0007$10.00/0 doi:10.1053/pi.2000.6229
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babesiosis has been recognized as an emerging endemic disease in the northeastern and northern midwestern United States, with sporadic cases reported in the Far West and in Europe, Africa, and Asia.6-19
Epidemiology Geographic Range Babesia species have a wide host and geographic range. In general, B bovis, B bigemina, B divergens, and B major infect cattle; B equi infects horses; B canis infects dogs; B felis infects cats; and B microti infects rodents.3 Four species are known to cause disease in humans. B microti, WA-1 (a strain originally isolated from a resident of Washington State and very closely related to B gibsoni), and MO 1 (isolated from a resident of Missouri and closely related to B divergens) are the causative agents in the United States, whereas B divergens and B bovis are found in Europe. In the United States, most human cases have been reported from the coastal areas of southern New England and eastern Long Island, but others have been reported in California, Minnesota, Missouri, New Jersey, Wisconsin, and Washington State.5-16 The number of cases of babesiosis appears to be increasing in endemic areas in the northeastern United States.6,8-10 In one study of a highly endemic area, approximately 9 percent of the population had evidence of previous B microti infection, compared with 11 percent with previous Lyme disease (Fig 1).10 The public health significance of zoonotic babesiosis may be greater than previously estimated.
Babesiosis in Children B microti is transmitted by the same Ixodes tick that transmits Borrelia burgdorferi, the causative agent of Lyme disease. Children have a higher incidence of Lyme disease than does any other age group. Despite such evidence of intense exposure to these ticks,
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Figure 1. Age related distribution of babesiosis and Lyme borreliosis in an endemic area. Age distribution of residents on Block Island, Rhode Island whose sera reacted with Babesia microti antigen (dark bars) and those whose sera reacted with Borrelia burgdorferi antigen (stippled bars). There was no significant difference in the percentage of children (n ⫽ 52) and adults (n ⫽ 522) whose sera reacted to B microti antigen and B burgdorferi antigen. (Reproduced by permission of PEDIATRICS, Vol. 89 Pages 1045-1048 Copyright 1992.10) only five children have been described with babesiosis, compared with hundreds of reported cases in adults.10,20-22 To resolve this apparent paradox, we conducted a prospective serosurvey of B microti antibody in residents of Block Island, Rhode Island (a
site in which the infection is endemic) and reviewed data from a large-scale retrospective Lyme disease and babesiosis serosurvey in Connecticut.10 The percentages of children seropositive to B microti on Block Island and in Connecticut (12 and 16 percent, respectively) were similar to those of adults (8 and 22 percent, respectively) (Fig 1). We concluded that children in both areas were exposed to babesial infection about as frequently as were adults. Interestingly, we found that of those seropositive for B microti, children reported an illness compatible with babesiosis at a greater rate than did adults, although the numbers were insufficient to predict rigorous correlation of disease severity with age. Despite such data and published reports that babesiosis in children may result in serious episodes of disease, it is unclear whether the relatively small numbers of reported babesial cases in children is caused by milder illness, an increased familiarity of babesiosis on the part of physicians caring for adults, or a more aggressive workup of fever in adults, including evaluation for babesiosis.10
Transmission and Immunity Babesial parasites usually are transmitted by hard-bodied ticks of the Ixodes genus. In the northeastern United States, B microti is transmitted by I dammini (also known as I scapularis).8 The precise vector for WA-1 has not been identified, but it is
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Figure 2. Life cycle of I dammini. (Reprinted, with permission, from the Annual Review of Entomology, Volume 30 娀1985 by Annual Reviews www. AnnualReviews.org.8)
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suspected to be I pacificus.12 Bovine babesiosis is transmitted by I ricinus in Europe.17 The life cycle of I dammini spans 2 years and has 3 active stages: larva, nymph, and adult (Fig 2). Each stage takes a blood meal from a vertebrate host to mature to the next stage. Disease usually is transmitted to humans by the nymph between May and September, but occasionally it is transmitted by the adult tick outside the usual transmission season. The major reservoir host of B microti in the northeastern United States is the white-footed mouse (Peromyscus leucopus). The white-tailed deer (Odocoileus virginianus) is the principal host of the adult tick. Rarely, babesiosis is acquired through blood transfusion.23-25 Whole blood, frozen erythrocytes, and platelets have been implicated. Transplacental-perinatal transmission of babesiosis also has been described.20 Immunity after babesial infection is incomplete. Low-level parasitemia may exist for months to years in cattle and as long as 26 months in humans after recovery from the initial illness.26 The spleen plays a critical role in protection against Babesia species. Most fatal cases of babesiosis in humans have occurred in splenectomized individuals, although asplenia does not always result in death or even severe illness.27 The spleen is thought to protect against babesial infection by removing and phagocytizing parasites from infected erythrocytes and by the production of antibabesial antibody. Other host defense mechanisms that may help limit babesial infection include T and B lymphocytes, antibody, complement, macrophages and macrophage products such as tumor necrosis factor (TNF), and polymorphonuclear leukocytes.15
Symptomatology Nature, Duration, and Course In the natural reservoir (white-footed mouse), B microti may be detected as early as 1 to 2 days after infective ticks have completed feeding. The time from infection until onset of symptoms (incubation period) is estimated to be 1 to 6 weeks for tick-borne transmission and 6 to 9 weeks for transfusion cases.7,23 Often, the patient has no recollection of a tick bite because the
unengorged I dammini nymph is only about 2 mm in length (Fig 3). The clinical severity of babesiosis includes subclinical infection, nonspecific flu-like illness, moderately severe malaria-like illness, and, in rare instances, fulminating disease resulting in death. Inapparent or mild infection is the most common form of the disease, as suggested by serosurvey data from endemic areas.7,9,10 Typical symptoms in moderate-to-severe infection include intermittent fever with a temperature as high as 40°C (104°F) and one or more of the following: chills, sweats, myalgia, arthralgia, nausea, and vomiting.7,28-30 Less commonly noted are emotional lability and depression, hyperesthesia, headache, sore throat, abdominal pain, conjunctival injection, photophobia, weight loss, and nonproductive cough. Unlike plasmodium merozoites, which are released from erythrocytes in synchrony, Babesia species reproduce by asynchronous, asexual budding. This asynchrony decreases the possibility of sudden extensive hemolysis and explains the lack of periodicity of symptoms that characterizes malaria. The findings on physical examination generally are minimal, often consisting only of fever. Mild splenomegaly, hepatomegaly, or both are noted occasionally.28-30 Slight pharyngeal erythema, jaundice, retinopathy with splinter hemorrhages, and retinal infarcts also have been reported. Unlike other tick-borne illnesses such as Lyme disease, Rocky Mountain spotted fever, or tularemia, rash seldom is noted. Patients with babesiosis have been reported with erythema chronicum migrans (ECM), but these patients most likely had concurrent Lyme disease. Several abnormal laboratory findings in patients with babesiosis reflect the invasion and subsequent lysis of erythrocytes by the parasite. Mild to moderately severe hemolytic anemia is common, with an elevated reticulocyte count.28 Elevated liver function tests occur in approximately one-half the patients. The leukocyte count is normal to slightly decreased, with a ‘‘left shift.’’ Atypical lymphocytes may be noted on manual differential blood smear examination. Thrombocytopenia is typical.28 The erythrocyte sedimentation rate is elevated. Proteinuria and elevated blood urea nitrogen (BUN) and creatinine levels also may be noted.
Figure 3. I dammini ticks (also known as I scapularis). From left to right, adult male, adult female, blood engorged female. A common pin is shown for size comparison.
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Babesiosis Table 1. Diversity and Duration of Disease in Symptomatic Subjects From Block Island and Connecticut Infected by the Agents of Lyme Disease (Borrelia) Alone, of Human Babesiosis (Babesia) Alone, and of Both Pathogens Detected Simultaneously
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ecchymoses, petechiae, congestive heart failure, pulmonary edema, renal failure, adult respiratory distress syndrome, and coma.27 The severity of human illness appears to correlate with age. Although babesial infection appears to be less severe in children than in adults, moderate-to-severe babesiosis may occur in children. Several cases of neonatal babesiosis have been described.20,22 One infant was severely ill, and the others were moderately ill with fever (temperature as high as 40°C) and irritability. Other findings included lethargy, tachypnea, pallor, poor feeding, jaundice, splenomegaly, and hepatomegaly. Common laboratory findings included anemia, thrombocytopenia, and increased levels of bilirubin and liver enzymes.
Complications Babesiosis usually lasts for a few weeks to several months, with prolonged recovery of up to 18 months. Parasitemia may continue even after the patient feels well. It has been found to persist in humans for as long as 17 months, and relapse of illness, as noted with malaria, has been noted 26 months after the initial episode (Fig 4).26 Patients with severe babesiosis may have a fatal outcome. In an epidemiological study of 136 cases of babesiosis from Long Island, New York, 7 patients (5 percent) died.11 The patients with fatal illness ranged in age from 60 to 82 years. Only one was known to be immunocompromised (cirrhosis). Although no reports of well-described long-term morbidity caused by babesiosis exist, anecdotal reports suggest that some patients have prolonged fatigue after acute illness.
Diagnosis Babesiosis should be suspected in any patient with an unexplained febrile illness who has recently lived or traveled to an endemic region during May through September, with or without
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Special Groups at Risk Patients at risk for severe disease include those who lack a spleen, are infected with HIV, are older than 50 years, or are coinfected with the agents of Lyme disease or ehrlichiosis.27,30-32 Coinfection with babesiosis in patients with Lyme disease is common in endemic areas of southern New England, occurring in approximately 10 to 15 percent of all Lyme disease cases.9,30 A recent study has shown that patients with coinfection of babesiosis and Lyme disease have more symptoms and are ill for a longer time than those with either infection alone (Table 1).30 Individuals with prior splenectomy generally have a severe form of B microti babesiosis that consists of fulminant illness lasting approximately a week and ending in death or a prolonged convalescence. Signs and symptoms include high fever, hemolytic anemia, hemoglobinemia and hemoglobinuria, jaundice,
Figure 4. Persistence of DNA amplifiable by polymerase chain reaction (PCR) in the blood of B microti–infected subjects who received specific antibabesial therapy as compared with subjects who received no such treatment. The 22 subjects treated with clindamycin and quinine had a shorter duration of parasitemia than did the 24 untreated subjects (P ⫽ .05 by the log-rank test). (Reprinted by permission of The New England Journal of Medicine. Krause PJ, Spielman A, Telford S, et al: Persistent parasitemia following acute babesiosis. N Engl J Med 339:160165, 1998.26 Copyright 娀1998 Massachusetts Medical Society. All rights reserved.)
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a history of tick bite. During the acute phase of babesiosis, definitive laboratory diagnosis can be made by direct identification of the causative agent in Giemsa-stained peripheral blood smears. The predominant forms in most blood smears are small (1.0-5.0 µm in length), round to oval ring-shaped intraerythrocytic structures that closely resemble those of Plasmodium species (Fig 5).15 Although uncommon, tetrad forms (Maltese-cross) are pathogenomonic of the disease, which together with the presence of extracellular merozoites and absence of pigment granules in infected erythrocytes distinguish them from Plasmodium. Multiple examination of both thick and thin smears is preferable because most documented cases of human babesiosis have had a low parasitemia. The level of parasitemia usually ranges between 1 and 10 percent in normal hosts and up to 85 percent in asplenic and other high-risk individuals. Specific diagnosis of babesiosis can be made by serological evaluation. Of the commonly used serologic tests, indirect immunofluorescent assay (IFA) is the most reliable.33-35 Patients with a babesial antibody titer of 1:32 or higher generally are considered to be seropositive, whereas those with a titer of 1:1,024 or greater usually are actively or recently infected. Cross-reactivity with other Babesia species and Plasmodium can occur. An IgM IFA test is available and suitable for routine clinical diagnosis of acute babesiosis.35 Thus, serology may quickly confirm a diagnosis of babesiosis when parasites are scarce or not detectable. In cases that are difficult to diagnose by smear or serology, detection of even mild parasitemia can be accomplished by inoculating the patient’s blood into a hamster.36 Parasitemia is amplified to detectable levels within the hamster from 2 to 4 weeks after inoculation. This method of confirmatory diagnosis requires a specialized laboratory. The polymerase chain reaction (PCR) should supplant the hamster inoculation test when laboratory proficiency and certification mechanisms are instituted.37,38 In experienced hands, PCR sensitively and specifically detects Babesia DNA within an afternoon.
Differential Diagnosis The clinical manifestations of malaria most closely resemble those of babesiosis, but malaria is less likely if the patient has not traveled recently to a malarious area. Babesial parasites can be distinguished readily from those of malaria on thin blood smear by an experienced microscopist. The initial clinical presentation of other tick-borne pathogens such as Lyme disease and ehrlichiosis may resemble that of babesiosis. Babesiosis is not associated with a rash, however, and other tick-borne pathogens seldom cause anemia.
Therapy Because of frequent misdiagnosis of babesiosis as P falciparum infection, chloroquine was commonly used in the very first babesiosis cases; however, it often fails to clear parasitemia and is not recommended for use in babesiosis. The combination of clindamycin and quinine is the current therapy of choice for babesiosis. This combination was used initially in the first reported case of babesiosis in a child, an 8-week-old who contracted babesiosis from a blood transfusion.24 Initially, she was thought to have malaria. Clindamycin (20 mg/kg/d) and quinine (25 mg/kg/d) were given after failure with chloroquine. Her favorable outcome suggested the prospective use of this combination in adults. Subsequently, numerous children and adults have been treated with clindamycin and quinine, with prompt clearing of parasitemia and resolution of clinical signs and symptoms.39 Treatment failures have been reported for this regimen, however, particularly in patients infected with human immunodeficiency virus (HIV). Preliminary results of a prospective, randomized treatment trial suggest that atovaquone (750 mg every 12 hours) and azithromycin (500 mg on day 1, then 250 mg/d thereafter) is as effective as clindamycin (600 mg every 8 hours) and quinine
Figure 5. Ring forms of B microti in human blood film (original magnification, ⫻1000).
Babesiosis (650 mg every 8 hours) for treatment of adults with babesiosis but is associated with fewer reported adverse events.40 Exchange blood transfusions have been used successfully in splenectomized patients with life-threatening babesiosis41 and can rapidly decrease parasitemia and remove toxic byproducts of babesial infections. Exchange transfusion should be used only in the most severe infections, such as in patients with a high parasitemia (more than 5 percent) and coma, hypotension, congestive heart failure, pulmonary edema, or renal failure. In combination with clindamycin and quinine, it is the treatment of choice for all cases of B divergens babesiosis. Quantitating parasitemia would seem to be critical in managing individuals with severe babesiosis, such as those with asplenia or HIV. Blood smears should be examined every 4 hours after administration of the first dose of clindamycin and quinine, and alternative therapy should be considered if parasitemia does not appear to decline appreciably within 24 hours.
Prevention Prevention of babesiosis can be accomplished by avoiding areas in May through September where ticks, deer, and mice are known to thrive. Especially important for those at increased risk in endemic areas, such as asplenic individuals, is avoidance of tall grass and brush where ticks may abound.8 Use of clothing that covers the lower part of the body and that is sprayed or impregnated with diethyltoluamide (DEET), dimethyl phthalate, or permethrin (Permanone) is recommended for those who travel in the foliage of endemic areas. A search for ticks on people and pets should be performed and the ticks removed as soon as possible. The latter is accomplished best by removal with tweezers by grasping the mouth parts without squeezing the body of the tick.42 Deer reduction might serve to diminish drastically human risk of tick-borne infection in a community. Deer were virtually eliminated on Great Island off Cape Cod, Massachusetts, and within 3 to 5 years the density of I dammini ticks decreased precipitously.43 Only one case of Lyme disease has been reported from that site since deer reduction. Host-seeking ticks may be killed by applications of acaricide to vegetation around yards or by targeted application using impregnated cotton, which mice carry back to their nests (Damminix). Prospective blood donors who reside in endemic areas and who have a history of fever within the preceding 1 to 2 months should be excluded from giving blood to prevent transfusionrelated cases. No vaccine has yet been developed against B microti or B gibsoni (WA1).
References 1. Babes V: Sur L’hemoglobinurie bacterienne boeuf. Compt Rend Acad Sci 107:692-694, 1888 2. Smith T, Kilbourne FL: Investigation into the nature, causation, and prevention of southern cattle fever. US Dept Agr Bur Anim Indust Bull 1:1-301, 1893 3. Levine ND: The Protozoan Phylum Apicomplexa, vol 2. Boca Raton, FL, CRC Press, 1988 4. Skrabalo A, Deanovic A: Piroplasmosis in man. Report on a case. Doc Med Geogr Trop 9:11-16, 1957
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5. Western KA, Benson GD, Gleason NN, et al: Babesiosis in a Massachusetts resident. N Engl J Med 283:854-856, 1970 6. Dammin GJ, Spielman A, Benach JL, et al: The rising incidence of clinical Babesia microti infection. Hum Pathol 12:398-400, 1981 7. Ruebush TK II, Juranek DD, Chisholm ES, et al: Human babesiosis on Nantucket Island: Evidence for self-limited and subclinical infections. N Engl J Med 297:825-827, 1977 8. Spielman A, Wilson ML, Levine JF, et al: Ecology of Ixodes damminiborne human babesiosis and Lyme disease. Ann Rev Entomol 30:439-460, 1985 9. Krause PJ, Telford SR, Ryan R, et al: Geographical and temporal distribution of babesial infection in Connecticut. J Clin Microbiol 29:1-4, 1991 10. Krause PJ, Telford SR, Pollack RJ, et al: Babesiosis: An underdiagnosed disease of children. Pediatrics 89:1045-1048, 1992 11. Meldrum SC, Birkhead GS, White DJ, et al: Human babesiosis in New York State: An epidemiological description of 136 cases. Clin Infect Dis 15:1019-1023, 1992 12. Persing DH, Herwaldt BL, Glaser C, et al: Infection with a Babesia-like organism in the western United States. N Engl J Med 332:298-303, 1995 13. Steketee RW, Eckman MR, Burgess EC, et al: Babesiosis in Wisconsin: A new focus of disease transmission. JAMA 253:26752678, 1985 14. Herwaldt BL, Persing DH, Precigout EA, et al: A fatal case of babesiosis in Missouri: Identification of another piroplasm that infects humans. Ann Intern Med 124:643-650, 1995 15. Krause PJ: Babesiosis, in Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Diseases, vol 2 (ed 4). Philadelphia, PA, Saunders, 1998, pp 2432-2437 16. Eskow ES, Krause PJ, Spielman A, et al: Southern extension of the range of human babesiosis in the eastern United States. J Clin Microbiol 37:2051-2052, 1999 17. Garnham PCC: Human babesiosis: European aspects. Trans R Soc Trop Med Hyg 74:153-155, 1980 18. Bush JB, Isaacson M, Mohamed AS: Human babesiosis: A preliminary report of two suspect cases in southern Africa. S Afr Med J 78:699, 1990 (letter) 19. Hsu NHM, Cross JH: Serologic survey for human babesiosis on Taiwan. J Formos Med Assoc 76:950-954, 1977 20. Esernio-Jenssen D, Scimeca PG, Benach JL, et al: Transplacental/ perinatal babesiosis. J Pediatr 110:570-572, 1987 21. Mathewson HO, Anderson AE, Hazard JGW: Self-limited babesiosis in a splenectomized child. Pediatr Infect Dis 3:148-149, 1984 22. Scimeca PG, Weinblatt ME, Schonfeld G: Babesiosis in two infants from eastern Long Island, N.Y. Am J Dis Child 140:971, 1986 (letter) 23. Mintz ED, Anderson JF, Cable RG, et al: Transfusion-transmitted babesiosis: A case report from a new endemic area. Transfusion 31:365-368, 1991 24. Wittner M, Rowin KS, Tanowitz HB, et al: Successful chemotherapy of transfusion babesiosis. Ann Intern Med 96:601-604, 1982 25. Gerber MA, Shapiro ED, Krause PJ, et al: The risk of acquiring Lyme disease or babesiosis from a blood transfusion. J Infect Dis 170:231-234, 1994 26. Krause PJ, Spielman A, Telford S, et al: Persistent parasitemia following acute babesiosis. N Engl J Med 339:160-165, 1998 27. Rosner F, Zarrabi MH, Benach JL, et al: Babesiosis in splenectomized adults: Review of 22 reported cases. Am J Med 76:696-701, 1984 28. Sun T, Tenenbaum MJ, Greenspan J, et al: Morphologic and clinical observations in human infection with Babesia microti. J Infect Dis 148:239-248, 1983 29. Benach JL, Habicht GS: Clinical characteristics of human babesiosis. J Infect Dis 144:481, 1981
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30. Krause PJ, Telford S, Spielman A, et al: Concurrent Lyme disease and babesiosis: Evidence for increased severity and duration of illness. JAMA 275:1657-1660, 1996 31. Benezra D, Brown AE, Polsky B, et al: Babesiosis and infection with human immunodeficiency virus (HIV). Ann Intern Med 107:944, 1987 (letter) 32. Falagas ME, Klempner MS: Babesiosis in patients with AIDS: A chronic infection presenting as fever of unknown origin. Clin Infect Dis 22:809-812, 1996 33. Chisholm ES, Ruebush TK II, Sulzer AJ, et al: Babesia microti infection in man: Evaluation of an indirect immunofluorescent antibody test. Am J Trop Med Hyg 27:14-19, 1978 34. Krause PJ, Telford SR, Ryan R, et al: Diagnosis of babesiosis: Evaluation of a serologic test for the detection of Babesia microti antibody. J Infect Dis 169:923-926, 1994 35. Krause PJ, Ryan R, Telford S: Efficacy of an IgM serodiagnostic test for the rapid diagnosis of acute babesiosis. J Clin Microbiol 34:20142016, 1996 36. Etkind P, Piesman J, Ruebush TK: Methods for detecting Babesia microti infection in wild rodents. J Parasitol 66:107-110, 1980 37. Persing DH, Mathiesen D, Marshall WF, et al: Detection of Babesia
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