On July 30, 2002, an 82-year-old man in Kitsap County (a peninsula of estuarine lowlands in Puget Sound, in western Washington), was admitted to a community hospital. During the previous 4 days, he had noted the gradual onset of chills (without fever), weakness, malaise, anorexia, dysphagia, marked thirst, and urinary dribbling. Until April or May 2002, he had been an avid jogger. Although he had not had the energy to jog thereafter, he had continued to walk his dog daily; they walked on a road around a lake that abutted his backyard, which he kept “natural,” and on a neighbor’s wooded property. He had an outdoor cat; had occasionally noted deer and (in previous years) voles or shrews in his yard; did not live near cattle; and had not traveled outside of Kitsap County or Mason County, the adjacent southern county, in the previous couple of years. He had not noted ticks on his body or received blood transfusions. His medical history included longstanding hypertension; secondary renal insufficiency; and incidental splenectomy in approximately 1990, when his distal pancreas, which had a benign mass, was removed.

When he was hospitalized on July 30, his temperature was 38.5°C; pulse, 76 beats/min; blood pressure, 168/94 mm Hg; and respiratory rate, 18 breaths/min. He had scleral icterus and dry mucous membranes from severe dehydration. The salient laboratory data and information about his clinical course are provided in Table 1. Initial laboratory testing showed many abnormalities, including marked thrombocytopenia and elevated values of creatinine, bilirubin, and lactate dehydrogenase.

Babesiosis was diagnosed, when a peripheral smear made on July 31 from blood collected on July 30 was noted to have intraerythrocytic, ring-like trophozoites; the level of parasitemia on a smear of fresh blood from July 31 was 41.4% (Table 1; Figure 2). On July 31, antibabesial therapy was begun at the community hospital; he received one dose of clindamycin (1,200 mg, by intravenous infusion) and one dose of quinine sulfate (975 mg, by mouth; the intended—i.e., ordered—dose was 650 mg).

Later on July 31, he was transferred to the University of Washington Medical Center. He continued therapy with clindamycin and quinine, with periodic adjustments of the dosage regimen (Table 1 footnote). In addition, he was transfused with 6 U of platelets and 4 U of packed erythrocytes. His acute renal failure (Table 1) was treated with hemodialysis; it was attributed to acute tubular necrosis from dehydration and intravascular hemolysis, superimposed on chronic renal insufficiency from hypertensive nephrosclerosis. His hospital course was also notable for laboratory evidence, on August 1, of asymptomatic, subendocardial ischemia and for pulmonary edema.

After he was discharged from the hospital on August 9, he continued antibabesial therapy through August 26 (Table 1) and hemodialysis through early September. He resumed jogging and walking in early October 2002 and had remained well as of July 2003.

This case of babesiosis had several unusual features. First, it occurred in Washington State, rather than in the Northeast, where most of the reported U.S. cases of zoonotic babesiosis have occurred. Our case raises the count for reported cases of babesiosis in Washington from three to four (one bloodborne and three presumably tick-borne cases). Second, the case was caused by a parasite most closely related, by molecular criteria, to B. divergens, a European bovine parasite (24), rather than to WA1-type parasites, which caused the three previously reported cases of babesiosis in the state. Third, the patient whose case we describe survived, despite having multiple risk factors for severe babesiosis and death: he was elderly (82 years old), was asplenic, had a high level of parasitemia (41.4%), and had multiorgan dysfunction that included renal failure.

Few cases of babesiosis in the western United States have been reported previously; all occurred in Washington or California. They include two tick-borne cases in California in 1966 (25) and 1979 (26), as well as seven tick-borne and two blood-transfusion–associated cases in California and Washington from 1991 to 2000 (7–11). Whereas the etiologic agents of the cases in 1966 and 1979 were not determined, the last nine cases were caused by the CA1- and WA1-types of Babesia- (or Babesia-like) piroplasms, which are distinct from each other but in the same phylogenetic group. Although the appropriate position for this clade in phylogenetic analyses of the piroplasms remains unclear (14), the position is remote from B. microti and B. divergens (11,14) (Figure 1).

The molecular characterization of our patient’s parasite (Washington, 2002) showed that the sequence for the complete 18S rRNA gene differs by eight bases from that of B. divergens (similarity score, 99.5%). In addition, serologic (Table 2) and morphologic (Figure 2) data support the conclusion that the patient was infected with a B. divergens–like parasite.

B. divergens infects cattle in Europe but has never been reported to do so in the United States. The parasite that caused the index bovine case of B. divergens infection, which was described in 1911 (27), is unavailable for molecular characterization. However, the DNA sequences of the complete 18S rRNA gene for bovine isolates of B. divergens from three European countries (6) and an isolate from an infected Ixodes ricinus tick from another European country (N.J. Pieniazek, unpub data) are identical; sequence data for the complete 18S rRNA gene of B. divergens from its tick vector have never previously been reported.

B. divergens has traditionally been considered not only a bovine parasite but also the etiologic agent of most of the reported zoonotic cases of babesiosis in Europe; the cases purportedly caused by B. divergens typically have occurred in asplenic persons who died if not appropriately and expeditiously treated (5). The type and quality of the evidence used to support the conclusion that B. divergens caused the zoonotic cases have varied markedly (5,6). To our knowledge, sequence data for the 18S rRNA gene have been reported for only two such cases. For one of the two cases (28), sequence data for the complete 18S rRNA gene were reported (EMBL data base no. AJ439713; data for 1,728 bases), which were not identical to the sequence for bovine B. divergens (6). For the other case (29), sequence data for a portion of the gene were reported (GenBank no. AF435415; data for 369 bases). Some of the European zoonotic cases attributed to B. divergens infection might have been caused by EU1, the etiologic agent of the first reported zoonotic cases of babesiosis in Italy and Austria, which ocurred in 1998 and 2000, respectively (6). In phylogenetic analysis, EU1 is most closely related to B. odocoilei (17,19) and is secondarily related to B. divergens (31 base differences) (6).

Besides our case, two other U.S. zoonotic cases have been attributed to infection with B. divergens–like organisms, on the basis of sequence data for the 18S rRNA gene (12,13). The first, a fatal case in Missouri in 1992, occurred in a 73-year-old asplenic man, whose parasitemia level was 3%–4% (12). In the original description of the case and the etiologic agent (MO1, for “Missouri 1”) (12), molecular data were provided for only a 128-bp fragment (with three unresolved positions), in which MO1 and B. divergens have identical sequences (6,12). The other U.S. case occurred in Kentucky in 2001, in a 56-year-old asplenic man, with a parasitemia level of 30% to 35% (13). The sequence of the complete 18S rRNA gene of the etiologic agent reportedly differs by three bases from that for B. divergens (similarity score, 99.8%). However, because no GenBank accession number was provided (13), we do not know whether the three base differences constitute a subset of the eight we found between our patient’s parasite and B. divergens.

We do not know enough about the biology of the etiologic agents of these three U.S. cases attributed (by molecular criteria) to infection with B. divergens–like parasites, to conclude how closely related the parasites are to the European bovine B. divergens. Various wild ruminants in the United States and Europe have been found to be infected with parasites that are considered B. divergens–like in some respects (e.g., are in the same phylogenetic clade, demonstrate serologic cross-reactivity in IFA testing, have similar morphologic characteristics [Figure 2]). Some such parasites (e.g., B. odocoilei, a parasite of white-tailed deer [6,17,19]; 30 base differences from B. divergens [similarity score, 98.3%]) are known to be different species than B. divergens. However, the classification by species of some B. divergens–like parasites remains unresolved (6). For example, the sequence for the complete 18S rRNA gene for a reindeer Babesia sp. in Scotland differs by only four bases from that of B. divergens (similarity score, 99.8%). Although the organism is not known to cause overt disease in local cattle and did not infect jirds injected with several-day-old blood from infected reindeer (30), the biologic data available to date are not definitive. Until more parasites that are B. divergens–like by molecular criteria, such as the parasites that caused the three U.S. zoonotic cases, are identified and characterized in other respects, we will not know whether the parasites are synonymous with B. divergens or belong to a complex of related species or strains.

The public health importance of the B. divergens–like organism in Washington is not yet known and may take years to determine. Its biology, geographic distribution, ecology, tick vector, and animal reservoir host(s), as well as the prevalence of infection in nonhuman and human hosts, risk factors for infection and disease in humans, and clinical manifestations of infection must be further investigated. We have begun our search for the tick vector; however, no ticks were found in September 2002, after flagging for 18 person-hours near the patient’s house. Molecular analysis at CDC of DNA from 98 ticks of various species, from various animals and counties in Washington, showed that none were infected with the patient’s parasite, but 11 were infected with B. odocoilei (data not shown).

The clinical aspects of our patient’s case are notable, particularly the fact that he survived, despite critical illness. The extent to which host (e.g., advanced age) versus parasite factors contributed to the severity of the case are unknown. However, even B. microti, which traditionally has been considered less virulent than B. divergens in humans (i.e., B. microti infection often is asymptomatic or associated with mild, nonspecific symptoms), has been associated with critical illness and fatalities, particularly among elderly, asplenic, or otherwise immunocompromised, patients (3,4,31,32). His remarkably good physical condition for his age and the meticulous medical care he received likely contributed to his survival.

We cannot generalize from his case to conclude what constitutes optimal antimicrobial therapy for infection with the patient’s parasite. The one clinical trial in which the effectiveness of antimicrobial regimens for treatment of babesiosis was evaluated included only patients who were not severely ill and were infected with B. microti (33). Anecdotal data and extrapolation from the literature about treatment of malaria suggest that exchange transfusion may be beneficial for some critically ill patients, especially for those with signs of hemodynamic instability or high parasitemia levels (e.g., >10%) (31,34–36). The persistence of PCR positivity in our patient for at least 2 months after he completed therapy (Table 2) indicates he continued to have subpatent parasitemia, despite remaining clinically well. Persistence of PCR positivity after treatment of symptomatic cases of B. microti infection with clindamycin and quinine has also been reported (37,38); PCR positivity lasted a mean of 16 days in 22 such patients, about one third of whom had persistent positivity for >1 month (none for >3 months) (37).

The case we describe underscores several points for clinicians. First, the diagnosis of babesiosis should be considered for febrile persons with hemolytic anemia, regardless of where they live or have traveled. Second, babesiosis, which can be life threatening, can be caused by novel parasites not detected by serologic or molecular testing for B. microti or the WA1- or CA1-type parasites (i.e., for parasites previously recognized to cause zoonotic babesiosis in the United States). This fact underscores the importance of manual examination of smears of blood from patients who might have babesiosis. In most hospitals, blood smears are examined by machines rather than by laboratory staff, unless specific criteria are met by the patient, certain abnormalities are “flagged” by the machine, or manual examination is specifically requested. Third, thorough characterization of novel Babesia spp. is needed to advance our knowledge about zoonotic parasites and to facilitate development of laboratory methods for detecting such parasites in patients, participants in epidemiologic investigations, and ultimately, perhaps, blood donors. Characterization of novel Babesia spp. would be facilitated if clinicians with patients likely infected outside of the geographic areas known to be endemic for B. microti sent fresh, pretreatment, anticoagulated, whole blood specimens, by overnight mail, on wet ice packs, to a reference laboratory experienced in doing such work.