Incidence and Prevalence

The incidence of babesiosis has steadily increased over the past 25 years. In New York State, the first state to mandate the reporting of babesiosis, more than 2700 cases have been notified to the health authorities. About 640 cases were reported from 1986 to 2001, and more than 2100 cases were reported in the following decade. The sharp increase noted since 2005 results from the emergence of babesiosis in the Lower Hudson Valley (Dutchess, Putnam, and Westchester counties) combined with the maintenance of highly endemic foci on eastern Long Island (Nassau and Suffolk counties).⁶ Along the northeastern seaboard, babesiosis has emerged in areas that were once at the periphery of the “historical heartland,” namely Maine and New Hampshire to the north and Delaware and Maryland to the south. In the upper Midwest, particularly in Minnesota, the number of annual cases has been higher since 2005. Babesiosis caused by B. microti is now considered an emerging infectious disease in the United States.²

The emergence of babesiosis has been attributed to a cascade of environmental changes that have favored deer and ticks.² Owing to the lack of natural predators and the public outcry over hunting, deer herds have become larger. Because ticks feed on deer, tick popu­lations have thrived. As winters have become milder, ticks have survived in greater numbers. Culling deer herds was proposed, but this measure has been difficult to implement. Tick repellents are available, but their use has been insufficient to prevent the rise of human babesiosis.

The seroprevalence of antibodies against B. microti antigen varies by year, study site, and sample population but has consistently been high in endemic areas, such as Nantucket (1.9% among residents and visitors),⁷ Block Island (9% among residents),⁸ southern Connecticut (0.5% to 9% among blood donors),^8,9 Shelter Island (4.3% in blood donors; 4.4% to 6.9% among residents),¹⁰ and eastern Long Island (1% among residents).¹¹ In Minnesota, seroprevalence among blood donors has been reported at 2%.¹² Given that seroprevalence is much higher than prevalence of clinical babesiosis, asymptomatic infection is more common than has been recognized.⁷ At some sites, however, symptomatic infection may be the rule. A 10-year serosurvey and case finding study of Block Island residents revealed that 20% of adults and 40% of children infected with B. microti are asymptomatic or experience an illness that is so mild that medical attention is deemed unnecessary.⁸

B. microti is primarily acquired during the blood meal of the tick I. scapularis,¹³ but two thirds of people who experience Babesia infection do not recall a tick bite.^14,15 The nymphal stage is the primary vector for transmission and is most active from late spring to early summer (see “Microbiology”).^13,16 Because the latency period typically lasts from 1 to 6 weeks, half of cases are diagnosed in July and a fourth in August.^14,17 Some cases present as early as late spring. Cases that present in late summer or early fall may have acquired the infection from a nymph or an adult tick.

Risk Factors

Babesiosis caused by B. microti often is severe in individuals who present the following risk factors: age older than 50 years,^14,17,27 splenectomy,^14,17,28,29 HIV infection,^28,30,31 malignancy,²⁸ blockade of tumor necrosis factor-α (TNF-α) activity (infliximab, etanercept),^32,33 and immunosuppression associated with therapies for transplantation or cancer (particularly those using rituximab because it depletes B cells).^28,34 These risk factors pertain to the transmission of B. microti by ticks as well as blood transfusion. In the latter setting, given that most cases have a significant comorbidity, risk factors for TTB include conditions that require blood transfusion such as hematologic disorders, cardiovascular surgery or procedure, gastrointestinal disease, bleeding and surgery, and complications of prematurity.^19,22 Two thirds of TTB patients are older than age 50 years, but two thirds of those younger than age 40 years have a hereditary hematologic disorder, such as sickle cell disease, thalassemia major, or Diamond-Blackfan anemia.¹⁹

United States: Other Babesia Species

B. duncani and B. duncani–type organisms are the etiologic agents of human babesiosis along the northern Pacific Coast.³⁵ The index case (WA1) occurred in a 41-year-old normosplenic man from a forested area of south-central Washington State.³⁶ Four cases (CA1 to CA4), all splenectomized men in their 20s to 40s, were subsequently reported in the San Francisco Bay area.³⁷ The first case of TTB caused by B. duncani involved a 76-year-old normosplenic man who had received RBCs donated by a 34-year-old Washington State resident.³⁸ The second case was diagnosed in a premature male infant who received RBCs for anemia of prematurity.³⁹ The donor lived in the San Francisco Bay area and had vacationed in a rural area of central Oregon 3 months before donating. The third case involved a 59-year-old patient who had sickle cell disease and required RBC exchange transfusion.⁴⁰ The 67-year-old donor reported a possible tick bite during a hike in the San Francisco Bay area. To date, the vector for transmission of B. duncani remains unknown. Seroprevalence against B. duncani antigen ranges from 3.9% (among the enlisted men at the military fort where the CA1 case occurred; titers >1 : 320) and 4.8% (among neighbors of the WA1 case; titers >1 : 256) to 16.9% (south of the site where CA3 was acquired; titers >1 : 320). The incidence of B. duncani infection remains unclear because clinical cases have been too few to validate the serologic test.

Cases caused by B. divergens–like organisms have been documented in Missouri, Kentucky, and Washington State.^41–43 All three patients had been splenectomized and were older than age 50 years. These men engaged in outdoor activities but did not recall a tick bite. In two cases, the organisms were identical to piroplasms found in eastern cottontail rabbits, implying that Ixodes dentatus may be a vector for zoonotic transmission of B. divergens–like organisms.⁴⁴ In Tennessee, one case may have been caused by B. odocoilei, a parasite of white-tailed deer.⁴⁵

Europe: Babesia divergens

About 30 cases have been attributed to B. divergens, a parasite of cattle that is transmitted by the tick Ixodes ricinus.^46–48 Most cases occurred between May and October in France, Ireland, and Great Britain, particularly from regions with cattle. Isolated cases have been reported in Portugal, Spain, Sweden, Finland, and Croatia (including the index case).² Patients are typically residents of rural areas (farmers, foresters) or vacationers (campers, hikers, hunters). Nearly all patients are splenectomized and experience a severe illness; one had a rudimentary spleen. One mild case occurred in a normosplenic patient.⁴⁹ Transfusion-transmitted babesiosis caused by B. divergens has not been reported, but antibodies against B. divergens have been detected in healthy blood donors (0.8% in midwestern Germany) and in individuals with clinical or serologic Lyme borreliosis (4% in midwestern Germany; 13% in southeastern Sweden).^50,51

Europe: Other Babesia Species

Cases of B. venatorum infection have been reported in Italy, Germany, and Austria.^34,52,53 All four patients were men older than 50 years of age. Three had undergone splenectomy for Hodgkin’s disease and one for hairy cell leukemia. One patient had just begun chemotherapy for stage IIIA diffuse large B-cell lymphoma, whereas another was receiving rituximab for reactivation of Hodgkin’s disease. In three cases, a tick bite was the suspected mode of transmission. To date, the prevalence of asymptomatic infection remains unknown because B. venatorum antigen is not available and because B. venatorum sera recognize B. divergens antigen.⁵² B. venatorum is most closely related to B. odo­coilei, with which it forms a sister group to B. divergens.⁵² Attributed to B. divergens based on morphology and seroreactivity, some of the early cases of babesiosis may have been caused by B. venatorum. A recent asymptomatic case was identified in Poland, but the etiologic agent could not be conclusively identified as B. venatorum (or B. divergens) based on partial sequencing of the 18S rRNA gene.⁵⁴

The only case of B. microti infection autochthonous to Europe was reported in 2007 from Germany.⁵⁵ A 42-year-old woman presented with fever and chest pain 1 week after a first cycle of chemotherapy for acute myeloid leukemia (FAB M3). Intraerythrocytic parasites were observed on Giemsa-stained blood smears and were unequivocally identified as B. microti by full sequencing of the 18S rRNA gene. The patient had received numerous platelet concentrates during the 2-month period before diagnosis of babesiosis. The platelet concentrate transfused 6 days before diagnosis had been prepared from a blood donation by an individual who subsequently tested seropositive for B. microti. In support of the transmission of B. microti by contaminated blood products in Europe, serologic evidence of asymptomatic infection has emerged from midwestern Germany (1.7% among healthy blood donors; 8.3% among Lyme borreliosis patients and asymptomatic individuals with a positive Lyme borreliosis serology) and eastern Switzerland (1.5% among community residents).^50,56 Symptomatic B. microti infections have been documented in Austria, Czechoslovakia, France, and the Netherlands, but the patients most likely became infected while traveling in the northeastern United States.

Other Regions

A case of B. divergens–like infection was diagnosed in a splenectomized resident of the Canary Isles.^2,48 On the African continent, isolated cases have been reported in Egypt, Mozambique, and South Africa.² A case of U.S.-type B. microti has been documented in Australia.⁵⁷ In Japan, a patient became ill after a transfusion of blood donated by an asymptomatic resident of the nearby Awaji Island. The organism (Kobe-type) was closely related to U.S.-type B. microti.⁵⁸ B. microti–like organisms were also implicated in two cases in Taiwan.^59,60 In South Korea, a 75-year-old splenectomized woman who presented with fever and severe anemia was infected with a large Babesia species (KO1) that is closely related to organisms found in sheep.⁶¹ Three asymptomatic individuals were identified in the patient’s village. Cases caused by B. microti have been reported from western China, along the border with Myanmar.^61a Asymptomatic infections with Babesia spp. that infect domestic animals have been reported from Mexico (B. bigemina, B. canis) and Colombia (B. bigemina, B. bovis).²

The life cycle of I. scapularis has three active stages (larva, nymph, adult) and requires 2 years for completion.^2,13,47,48 In the fall, adult ticks feed primarily on white-tailed deer (Odocoileus virginianus). Deer are incompetent reservoir hosts for B. microti but are essential for maintenance of I. scapularis. Adult ticks overwinter in an engorged state and lay eggs in the spring. Because B. microti does not reach the ovaries of adult ticks should they be infected, eggs are free of B. microti (no transovarial transmission). Larvae hatch in late July and become infected as they feed in the fall on a wide range of vertebrates. The primary reservoir host for B. microti is the white-footed mouse (Peromyscus leucopus).¹³ Other competent reservoirs include short-tailed shrews, eastern chipmunks, and raccoons.⁶² Passerines, raptorial birds, and ground-dwelling birds (e.g., wood thrush, veery) are also reservoirs, although of lesser competence. Fed to repletion, larvae overwinter and molt into nymphs in late spring. If the larva is infected, so will be the nymph (trans-stadial transmission). Nymphs feed on P. leucopus and other vertebrates from May through July. The feeding of nymphs in early summer ensures that P. leucopus mice become reservoirs of B. microti for larvae that feed in late summer. In the fall, nymphs molt into adults.

Soon after attachment of the larva, B. microti–infected erythrocytes accumulate in its gut.^47,48,63 Pregametocytes mature into gametocytes. A novel endocytic organelle, the cytostome, forms. Microtubules accumulate at the anterior end of the organism to form a raylike structure that contributes to the fusion of gametocytes into zygotes. Using an arrowhead structure, zygotes penetrate the gut epithelium. The arrowhead structure dissociates, and zygotes translocate to the basal lamina. In the hemolymph, zygotes become ookinetes that travel to the salivary acini. There, ookinetes undergo hypertrophy into sporoblasts that remain dormant as long as the larva overwinters.

Transmission to Vertebrate Hosts

Larvae, nymphs, and adult ticks all feed on humans, but the nymph is the primary vector for B. microti transmission.^13,47,48 The small size of the nymph (<2.5 mm), its pale gray ground color, the inconspicuous feeding site, and the benign local reaction explain why recollection of a tick bite is uncommon.^14,15 As nymphs attach to the host, their temperatures rise. Sporogony is initiated, and the sporoblast membrane folds. After 48 hours, micronemes and rhoptries appear. Cytoplasm starts to bud from the parent sporoblast, and nuclear division ensues. During the last hours of feeding, which typically lasts 72 hours, as many as 100,000 sporozoites are deposited in the dermis of the host. Events that lead sporozoites toward the bloodstream are not well understood. Babesia sporozoites do not undergo merogony in an exoerythrocytic compartment but readily invade erythrocytes. Surface antigens mediate their initial attachment to the erythrocyte.⁶⁴ The erythrocyte membrane invaginates, leading to the formation of a parasitophorous vacuole that gradually disintegrates. The organism differentiates into a trophozoite that moves freely in the host cell cytoplasm and eventually undergoes binary fission, resulting in two to four merozoites (daughter cells; Fig. 283-1). Merozoites egress the erythrocyte, thereby triggering its lysis, and soon invade other intact erythrocytes.