Version May 2024
INTRODUCTION — Babesiosis is an infectious disease caused by protozoa of the genus Babesia and is transmitted primarily by tick vectors. Transmission rarely occurs through blood transfusion, solid organ transplantation, or congenitally. Babesia protozoa infect mammals and cause lysis of host red blood cells [1-4].
The microbiology, epidemiology, and pathogenesis of babesiosis will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of babesiosis are discussed separately. (See "Babesiosis: Clinical manifestations and diagnosis" and "Babesiosis: Treatment and prevention".)
MICROBIOLOGY — Babesia species have been classified into four clades [5-7]:
●Clade 1 contains Babesia microti organisms that cause human babesiosis, primarily in the United States. Cases also have been reported in Europe, Asia, and Australia. Initially considered as a single species, B. microti appears to be genetically diverse [7]. In fact, B. microti may be a genus on its own that ranks equally to the Babesia sensu stricto genus (clades 3 and 4, see below) [8].
●Clade 2 contains Babesia duncani (WA1, WA2, CA5, CA6) and B. duncani-related organisms (CA1, CA3, CA4), the main etiologic agents of human babesiosis along the West coast of the United States.
●Clade 3 contains Babesia divergens isolates from cattle in Europe, B. divergens-like organisms identified in humans in Europe and the United States, and Babesia venatorum, identified in humans in Europe and mainland China.
●Clade 4 contains Babesia species that can infect humans but usually are found in domesticated vertebrates. These include Babesia crassa-like organism and Babesia motasi-like organism, which typically infect sheep and goats [9,10].
The phylogenetic classification is generally consistent with classifications based on morphology and life cycle characteristics [3,5,11,12]. Trophozoites of Babesia in clades 1 and 2 are small in diameter (<3 microns) and form up to four merozoites arranged in a tetrad ("Maltese cross"). Transmission of Babesia in clades 1 and 2 is transstadial (eg, from larvae to nymphs and from nymphs to adults) but not transovarial (from adults to eggs), indicating that vertebrate hosts are an absolute requirement for their maintenance in the tick life cycle.
Trophozoites of Babesia in clades 3 and 4 typically are large in diameter (>3 microns) and form only two merozoites. Exceptions to these phenotypes within clade 3 include Babesia that infect humans, such as B. divergens, B. divergens-like organisms, and B. venatorum. In human red blood cells (RBCs), their trophozoites are small in diameter (<3 microns) and their merozoites can be arranged in tetrads [12-14]. Transmission of Babesia in clades 3 and 4 is both transovarial and transstadial, suggesting that vertebrate hosts are not essential for their short-term maintenance in the tick life cycle. These organisms are referred to as "true" Babesia species or as Babesia species "sensu stricto".
Both Babesia and Plasmodium parasites invade RBCs. They differ in that Plasmodium species are transmitted by mosquitoes from person to person, thereby using humans as reservoir hosts, have an exoerythrocytic (hepatic) stage, and leave hemozoin deposits in RBCs. In contrast, Babesia species are transmitted by ticks, are not transmitted from person to person but rather use mammals as reservoir hosts, lack an exoerythrocytic stage, and do not leave hemozoin deposits in RBCs [3,5,11,12].
EPIDEMIOLOGY
United States
Babesia microti — B. microti is the predominant etiologic agent of babesiosis in the United States [3]. White-footed mice (Peromyscus leucopus) have long been considered the primary reservoir host for B. microti but other small mammals, such as shrews and chipmunks, are competent reservoirs [15,16]. The primary vector for transmission of B. microti to humans is the nymphal stage of the Ixodes scapularis (figure 1 and figure 2).
Geography — Most cases of babesiosis (>98 percent) occur in ten states: eight in the Northeast (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island and Vermont) and two in the upper Midwest (Minnesota and Wisconsin) (figure 3) [17-20].
The states with the highest annual incidence between 2011-2019 were Rhode Island, Connecticut, and Massachusetts (13.4, 6.8, and 6.7 cases per 100,000 residents, respectively). The states with the highest number of cases during this same period were New York, Massachusetts, and Connecticut (4738, 4136, and 2200, respectively).
Incidence and prevalence — The incidence of babesiosis has increased considerably in the Northeast over the past three decades [21]. Babesiosis has been a nationally notifiable disease since January 2011. In 2019, babesiosis was a reportable condition in 40 states and the District of Columbia, and at least one case was reported in 25 of these states to the United States Centers for Disease Control and Prevention. The number of annual cases increased between 2011 and 2019 from 1126 to 2418 cases [20,22]. Babesiosis is expected to remain an emerging infectious disease for many years to come.
The increase in incidence has been attributed to several factors including expanding deer population with concomitant increased tick density, increased human habitat in wooded areas, and heightened community awareness. Deer numbers have increased due to reforestation, lack of predators, and insufficient culling of the herd.
Seroprevalence varies by location, year, time of year, and population surveyed (table 1). In the Northeast and the upper Midwest, B. microti seroprevalence in healthy blood donors has ranged from 0.5 to 16.0 percent. The discrepancy between seroprevalence and the prevalence of clinical disease suggests that asymptomatic and self-limited infection is common [23]. A carefully designed epidemiologic study found that about 20 percent of adults and 40 percent of children experience asymptomatic infection [24]. (See "Babesiosis: Clinical manifestations and diagnosis", section on 'Asymptomatic infection'.)
The prevalence of B. microti infection in nymphal I. scapularis ticks ranges from 1 percent (in newly endemic areas) to 20 percent (in some well-established areas) [25].
Transmission — B. microti is transmitted primarily by ticks and rarely by blood transfusion, solid organ transplantation, or transplacentally.
Tick bite — Most infections with B. microti are acquired through tick bite between May and September; more than three-fourths of cases are diagnosed from June through August [17,22,26,27]. The nymphal tick is the primary vector for transmission of infection, although adult ticks also transmit B. microti [3,11].
The life cycle of I. scapularis spans over two years and includes deer and small mammals, especially white-footed mice (figure 2 and figure 4):
●Adult female ticks lay eggs in the spring (year 1). B. microti infection is not transmitted from adult ticks to eggs.
●Tick eggs hatch and larvae appear in late July (year 1).
●Tick larvae feed on white-footed mice (P. leucopus, a primary reservoir for B. microti) in late summer (year 1). Red blood cells (RBCs) from infected mice (or other vertebrate hosts) accumulate in the mid-gut of the tick larva where Babesia gametocytes mature into gametes. Sexual reproduction involves fusion of one gamete with another. The resulting zygote invades the gut epithelium and becomes an ookinete. Ookinetes reach the hemolymph and migrate to the tick salivary glands where they hypertrophy into sporoblasts. Sporoblasts remain dormant while the larva overwinters.
●Tick larvae molt into nymphs in the spring (year 2). B. microti is transmitted from larvae to nymphs (transstadial transmission).
●Tick nymphs, the primary vector for B. microti transmission, feed on small mammals in early summer (year 2). They also feed on humans, but humans are dead-end hosts. Sporozoites are delivered to the host dermis 36 to 72 hours after nymphal attachment; therefore, tick removal during the first 24 hours of attachment eliminates the risk of transmission. Sporozoites migrate to the bloodstream where they invade erythrocytes and undergo asexual replication to yield merozoites. Merozoites are released into the bloodstream and invade nearby erythrocytes. (See "Babesiosis: Clinical manifestations and diagnosis", section on 'Microscopy'.)
●Tick nymphs molt into adults in the fall (year 2).
●Adult ticks feed on white-tailed deer (Odocoileus virginianus) in the fall (year 1). Deer are not competent reservoirs for B. microti but are critical for expansion of the tick population because adult ticks mate on deer, and female ticks take a blood meal on deer which provides sufficient protein to lay eggs in the spring. Adult ticks occasionally feed on humans.
Transfusion of blood products — Babesiosis may be transmitted by transfusion of blood products from asymptomatic donors. Most cases of transfusion-transmitted babesiosis occur from June through November (consistent with the seasonality of tick-acquired babesiosis) [28,29]. Transfusion-transmitted babesiosis may occur at any time of year, however, because asymptomatic infection can persist for more than a year and because the incubation period after blood transfusion can be as long as six months. Transfusion-transmitted babesiosis usually is reported from endemic areas but can occur outside of endemic areas when donors residing in nonendemic areas become infected while traveling in endemic areas or when contaminated blood products donated in endemic areas are exported to nonendemic areas [28]. (See "Blood donor screening: Laboratory testing", section on 'Babesia microti'.)
More than 250 cases of transfusion-transmitted babesiosis have been reported [2,28,30,31]. The largest series of transfusion-transmitted babesiosis included 159 patients; the median age was 65 years, two-thirds of patients were >50 years, and 10 percent were neonates [28]. Approximately 20 percent of these cases were fatal.
Transfusion-transmitted babesiosis often is severe because recipients of blood products are often immunocompromised or have coexisting medical conditions. The most frequent conditions or procedures associated with transfusion-transmitted babesiosis include hematologic disorders, cardiovascular surgery or procedures, gastrointestinal bleeding or surgery, and complications of prematurity in the newborn. Transfusion-transmitted babesiosis also has occurred in patients who have undergone post-traumatic splenectomy or organ transplantation [28].
Most cases of transfusion-transmitted babesiosis have involved packed RBCs. A small number of cases have been attributed to whole blood-derived platelets [28]. Typically, liquid-stored RBCs are involved; frozen deglycerolized RBCs are seldom implicated. The median age of liquid-stored RBCs at time of transfusion has ranged from 4 to 42 days [32-35].
In May 2019, the US Food and Drug Administration recommended blood donor screening for B. microti with a licensed nucleic acid test in 14 states (Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, Wisconsin) and Washington, DC [33]. Licensed nucleic acid tests use transcription-mediated amplification technology; their 95 percent limit of detection ranges from 1.8 to 3.1 parasites per mL of blood [36,37]. In the year following implementation of the FDA recommendation by the American Red Cross (ARC), no cases of transfusion-transmitted babesiosis were reported to the ARC [31,38]. (See "Blood donor screening: Laboratory testing", section on 'Babesia microti'.)
Issues related to blood donor evaluation are discussed separately. (See "Blood donor screening: Laboratory testing", section on 'Babesia microti'.)
Solid organ transplantation — Transmission of B. microti infection by solid organ transplantation has been described in two renal transplant recipients from an organ donor who received multiple transfusions on the day he died from traumatic injuries [39].
Transplacental transmission — More than 10 cases of congenital infection with B. microti have been reported in the United States [40-48]. In all but two cases, infants were born at term and symptoms developed between the third and sixth week of age [40,45-47]. There was no history of tick bites for the neonates. In three cases, the mother recalled being bitten by a tick one to seven weeks prior to delivery. At the time of diagnosis, parasitemia typically ranged from 2 to 5 percent in the infants. Parasite DNA was amplified in the serum from two mothers and in the placental tissue from another. All infants and mothers had antibodies against B. microti antigen.
One case of congenital babesiosis provided definitive proof that B. microti can be transmitted vertically [41]. The mother was hospitalized at week 30 of gestation with a 10-day history of fever and rigors. Intraerythrocytic ring forms were noted in 9 percent of the mother's RBCs but also in the amniotic fluid that had been obtained without traversing the placenta. The mother delivered by emergency cesarean section due to fetal distress. Immediately following delivery, intraerythrocytic parasites were observed on smears of blood obtained from the neonate.
Management of (suspected) congenital babesiosis has consisted of atovaquone (40 mg/kg/day orally divided in two doses) plus oral azithromycin (10 or 12 mg/kg/day orally) for up to 10 days. Persistent anemia has been addressed by transfusion of packed RBCs.
Risk factors — Risk factors for babesiosis include residence in or travel to an endemic area within the previous six weeks or blood transfusion within the previous six months.
Risk factors for severe babesiosis include [26,27,49-51]:
●Asplenia or hyposplenism – Many fatal cases of babesiosis occur in asplenic individuals, although asplenia does not always result in severe disease.
●Immunosuppression caused by:
•HIV/AIDS with a low CD4 cell count
•Malignancy and/or cancer chemotherapy
•Immunosuppressive therapy for solid organ or stem cell transplantation
•Blockade of tumor necrosis factor-alpha (etanercept, infliximab)
•Depletion of mature B cells by anti-CD20 antibody (rituximab, ocrelizumab).
●Age – Most cases of severe babesiosis in otherwise healthy patients occur among individuals >50 years. Neonates are also at risk for severe disease.
Risk factors for relapsing babesiosis (despite a standard course of antimicrobial therapy) include malignancy (especially B cell lymphoma) or other conditions treated with rituximab, malignancy together with asplenia, solid organ or stem cell transplantation, and HIV/AIDS.
Coinfection with other tick-borne illnesses — Other pathogens transmitted by I. scapularis ticks include Borrelia burgdorferi, Anaplasma phagocytophilum, Borrelia miyamotoi, Borrelia mayonii, Powassan virus, and Ehrlichia muris-like agent. (See "Diagnosis of Lyme disease" and "Human ehrlichiosis and anaplasmosis" and "Borrelia miyamotoi infection" and "Arthropod-borne encephalitides", section on 'Powassan virus'.)
In babesiosis and Lyme disease endemic areas, about half (range 23 to 72 percent) of babesiosis patients experience Lyme disease coinfection, whereas about a tenth (2 to 40 percent) of Lyme disease patients experience concurrent babesiosis [1,25,52,53].
Other Babesia species — Uncommon Babesia species that cause human babesiosis in the United States include B. duncani and B. divergens:
●B. duncani and related organisms – B. duncani is closely related to Babesia conradae (a Babesia species of domesticated dogs in California) and to a Babesia species of wildlife mammals in the western United States [5]. The tick vector for B. duncani is thought to be Dermacentor albipictus [54]. B. duncani has caused sporadic disease along the West coast. Two cases of babesiosis due to B. duncani and related organisms have been described in Washington state, one case in Oregon, and six cases have been described in California [54-58]. Of these, five cases were attributed to tick bites and occurred in men ≤50 years; four of the five patients were asplenic [56,58]. The other three cases were acquired through blood transfusion [55,57,59]. The blood donors either had no symptoms or experienced mild symptoms (nausea, fatigue) prior to donation [55,57,59]. The incidence of B. duncani infection is uncertain [55,56,58].
●B. divergens-like organisms – Babesiosis due to B. divergens–like organisms was first described in a Missouri man [60]; subsequent cases were reported from Kentucky, Washington state, and Michigan [61,62]. A case of possible transfusion-transmitted infection has been reported from Arkansas [63]. All patients were asplenic and ≥50 years of age. The incidence of infection with B. divergens-like organisms is unknown but is likely to be low. In five cases, the causative organisms were identical to organisms obtained from eastern cottontail rabbits on Nantucket Island, Massachusetts [13]. The tick vector is thought to be Ixodes dentatus but has not been identified conclusively [3].
Europe — Cases of babesiosis in Europe have been reported sporadically.
B. divergens — The most common cause of babesiosis in Europe is B. divergens. Cattle are the main vertebrate host for B. divergens. About 40 cases of babesiosis in Europe have been attributed to B. divergens, mostly in France and Ireland, particularly in regions with cattle [12]. Individuals at risk include farmers, veterinarians, foresters, and vacationers engaged in outdoor activities. Isolated cases have been reported from Finland, Norway, Sweden, Poland, Spain, Portugal, and Croatia. The majority of cases occurred in asplenic individuals who became ill between May and September. Nearly all cases have been attributed to bites of the Ixodes ricinus tick; both nymphs and adult ticks are vectors.
Serosurveys have demonstrated 0.8 to 2.1 percent seroprevalence of B. divergens among healthy blood donors in Europe [12,63-65]. Among patients with clinical Lyme borreliosis or serological evidence of B. burgdorferi sensu lato infection, seroprevalence has ranged from 4 to 13 percent [64,66].
B. microti — The first autochthonous case of babesiosis due to B. microti was described in Germany and occurred in a 42-year-old woman who was receiving chemotherapy for acute myeloid leukemia and had received numerous platelet concentrates [67]. The incriminated unit was transfused six days prior to diagnosis of babesiosis and had been prepared from a blood donation by an individual who subsequently tested seropositive for B. microti. Additional autochthonous cases have been reported from northeastern Poland.
Most cases of babesiosis due to B. microti have occurred in travelers upon return to their home country (Austria, the Czech Republic, Denmark, France, and the Netherlands) from the northeastern United States. Asymptomatic infection has been described in Poland; B. microti most likely was acquired locally because the carriers were forestry workers [68].
B. microti infections may be under-recognized in Europe. Serosurveys have demonstrated a seroprevalence of 1.5 to 3.4 percent among healthy individuals in regions where I. ricinus ticks are endemic [64,69,70]. Among patients who had a history of tick bite and presented with fever and fatigue, 9 percent were seropositive for B. microti antibody [71]. Among patients with clinical evidence of Lyme borreliosis or serological evidence of B. burgdorferi sensu lato infection, seroprevalence was 11.5 percent [64].
B. venatorum — B. venatorum is closely related to Babesia odocoilei, a Babesia species of white-tailed deer in the United States [72]. In Europe, mammalian reservoirs include roe deer, and the tick vector is I. ricinus [73]. Five cases of babesiosis due to B. venatorum have been reported [14,72,74,75]. All patients were men ≥50 years and had undergone splenectomy because of Hodgkin's disease or hairy cell leukemia.
Sera from patients infected with B. venatorum cross-react with B. divergens antigen, raising the possibility that some of the cases attributed to B. divergens on the basis of serology were caused by B. venatorum [72]. In the absence of an immunofluorescence antibody test specific for B. venatorum, the incidence of infection with B. venatorum remains unknown.
B. crassa-like organism — B. crassa-like organisms have caused disease in one patient in Slovenia and another in western France. B. crassa is a parasite of goats and sheep. The vector for transmission to humans is unknown but may be Haemaphysalis concinna.
Asia — Babesiosis is increasingly reported from Asia, especially mainland China where B. venatorum, B. microti, and, B. crassa-like organism have been identified as human pathogens [10,76-81]:
●B. venatorum – B. venatorum is endemic in northeastern China. Isolates obtained from these patients are identical to those from Europe. The animal reservoir is unknown; the tick vector most likely is Ixodes persulcatus [76]. A single case was reported from northwestern China.
●B. microti – B. microti infection is found in southwestern China and in the Heilongjiang province in northeastern China [77,78,80,81]. Cases have been sporadically reported in Taiwan and Japan. The single case reported from Japan was caused by a Kobe-type organism; the vertebrate reservoir was the field mouse Apodemus speciosus but the tick vector remains unknown [82].
●B. crassa-like organisms – These organisms have caused endemic human disease in northeastern China. Isolates are closely related to those found in ticks of the region, including I. persulcatus and Haemaphysalis concinna. They also are closely related to those found in sheep in the same region [10].
●Babesia motasi-like organisms – Two cases have been reported from South Korea. The etiologic agent was initially referred to as K01 [9]. Both isolates are closely related to B. motasi, a species typically found in sheep [83]. Haemaphysalis longicornis is the presumed tick vector.
Other regions — Isolated cases of clinical babesiosis have been reported worldwide, including Australia, Brazil, Canada [84,85], the Canary Islands, Colombia, Egypt, Georgia (in the Caucasus region), India, Mexico, Mozambique, South Africa, and Turkey. Asymptomatic infections have been reported from Bolivia, Brazil, Colombia, Cuba, Mexico, and Mongolia [9,82,86-88].
PATHOGENESIS — The pathogenesis of Babesia species has been studied in animal models (mostly mice, cattle, and dogs) [89]. The release of merozoites from erythrocytes and associated loss of cell membrane integrity cause hemolysis that is associated with many of the clinical manifestations and complications of babesiosis, including fever, anemia, jaundice, hemoglobinuria, and renal insufficiency [2]. The spleen plays a critical role in protection against Babesia infection because it contains macrophages, which ingest and clear infected erythrocytes. (See "Babesiosis: Clinical manifestations and diagnosis".)
Hemolysis contributes to (but does not account entirely for) the anemia associated with babesiosis, which typically is more prolonged than parasitemia. Babesia parasites generate reactive oxygen species; membrane lipid peroxidation decreases red blood cell (RBC) deformability, thereby promoting RBC clearance by splenic macrophages [90]. Opsonization by autologous immunoglobulin G and perhaps complement factors also may contribute to RBC clearance [90,91]. Anemia is coupled with increased erythropoiesis as evidenced by reticulocytosis.
The role of antibodies in host defense against Babesia is not fully understood. Mouse models of B. microti infection indicate that antibodies are not critical for clearing parasites in immunocompetent hosts because lack of mature B cells in otherwise immunocompetent mice does not alter their resistance to B. microti [92,93]. In immunocompromised patients, however, antibodies appear to be of critical importance because patients treated with rituximab (anti-CD20) for B cell lymphoma or an autoimmune disorder are at risk for persistent or relapsing babesiosis. In these patients, resolution of parasitemia often coincides with seroconversion (following cessation of rituximab therapy) [14,94].
CD4+ T cells are central to host immunity in babesiosis. Babesiosis typically is severe in HIV-infected individuals [92,95,96]. In mice, interferon (IFN)-gamma is critical for host resistance to B. microti and B. duncani [92,95,96]. The main source of IFN-gamma appears to be CD4+ T cells in B. microti infection and NK cells in B. duncani infection. IFN-gamma increases surface expression of MHC class II molecules on antigen-presenting cells and induces or upregulates inflammatory cytokine gene expression.
Symptoms of babesiosis, such as fever, headache, and myalgia, are similar to viral-like illnesses and are suggestive of a host inflammatory response involving pyrogenic cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-6. Both cytokines were detected in the blood of a patient with mild babesiosis caused by B. microti [3,86]. Inflammatory cytokines also may contribute to the complications associated with severe babesiosis, such as acute lung injury. In mice infected with B. duncani, pulmonary manifestations include edema and intravascular margination of leukocytes [97]. In these mice, TNF-alpha is localized to the alveolar septa and IFN-gamma around and within pulmonary vessels [97]. Blockade of TNF-alpha prevents death of B. duncani-infected mice, whereas blockade of IFN-gamma promotes death in these mice [96,98].
SUMMARY
●Babesiosis is an emerging infectious disease due to protozoa of the genus Babesia that invade and lyse red blood cells (RBCs). The primary mode of transmission is a tick bite. Rarely, transmission occurs via blood transfusion, solid organ transplantation, or transplacentally. Babesia species are classified in four clades based on their molecular genetic characteristics. (See 'Introduction' above.)
●Babesia microti is the predominant species causing human babesiosis in the United States. Babesiosis due to B. microti is endemic in the northeastern United States (particularly in the coastal counties and on the islands off the coast of southern New England) and in the upper Midwest. (See 'United States' above.)
●The transmission cycle of B. microti includes ticks, mice, and deer. Adult Ixodes scapularis ticks feed on white-tailed deer, which are not competent reservoirs for B. microti but markedly amplify tick numbers. Tick larvae and nymphs feed on white-footed mice (a major reservoir for B. microti). Nymphs are primary vectors for transmission to humans, who are incidental hosts (figure 2). (See 'Transmission' above.)
●Babesia divergens is the principal species causing human babesiosis in Europe. The transmission cycle includes ticks and cattle, and the disease occurs sporadically. (See 'Europe' above.)
●Babesiosis is increasingly reported from Asia. The major causative species are Babesia venatorum, B. microti, and Babesia crassa-like organism. B. venatorum and B. crassa-like organisms are endemic in northeastern China. B. microti infection has been reported from northeastern and southwestern China. (See 'Asia' above.)
●A feeding tick introduces sporozoites into the dermis of the vertebrate host. Sporozoites eventually reach the circulation, where they invade RBCs. Within RBCs, sporozoites differentiate into trophozoites, and asexual replication of trophozoites generates two to four merozoites. Egress of merozoites is accompanied by rupture of the host RBCs. Free merozoites in turn invade nearby RBCs. (See 'Tick bite' above.)
●Anemia and fever are major features of babesiosis. Anemia results, in part, from the hemolysis of RBCs upon egress of merozoites. RBC clearance also may result from decreased deformability and/or from opsonization. Proinflammatory cytokines likely cause fever. (See 'Pathogenesis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Jeffrey A Gelfand, MD, FACP, who contributed to an earlier version of this topic review.
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