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The first recorded mention of babesiosis is believed to date to biblical times. In the Book of Exodus, the fifth plague is described as “very grievous murrain” that fell “upon thy cattle which is in the field, upon the horses, upon the asses, upon the camels, upon the oxen and upon the sheep.” Bovine babesiosis is still referred to as murrain in the Irish countryside. In 1888, the microbiologist and pathologist Victor Babes attributed the febrile hemoglobinuria and death of cattle in Romania to an intraerythrocytic microorganism. Soon after, Theobald Smith and Frederick Kilborne described a similar piroplasm ( L. pirum, “pear”) in the erythrocytes of Texas cattle with fever. Initially named Pyrosoma, this organism became known as Babesia bigemina. Smith and Kilborne also identified the tick Rhipicephalus annulatus as its vector, establishing for the first time that hematophagous arthropods can transmit an infectious agent to a vertebrate host. The first well-documented case of human babesiosis was reported in 1957 in a 33-year-old splenectomized herdsman who had been grazing cattle on tick-infested pastures near Zagreb, Croatia. The infection was fulminant and fatal. Originally identified as Babesia bovis, the causative agent was later reported to be Babesia divergens, a parasite of cattle. In 1969, a 59-year-old woman who had summered on Nantucket Island off the coast of Massachusetts presented with a history of fever, headache, and crampy abdominal pain. This patient had an intact spleen, and the causative agent was Babesia microti, a parasite of white-footed mice. Andrew Spielman and colleagues identified the vector as the deer tick Ixodes dammini (now recognized as Ixodes scapularis ). As the number of cases on the island grew, the disease became known as “Nantucket fever.” Babesiosis caused by B. microti is now recognized as endemic on the mainland of the United States, particularly in the Northeast and the upper Midwest.
Epidemiology
United States: Babesia microti
Geographic Distribution
Human babesiosis became a nationally notifiable disease in January 2011. Notification is made via the National Notifiable Diseases Surveillance System using the standard case definition developed by the Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists. In 2014, babesiosis was reportable from 31 states, of which 22 notified the CDC of at least one case. Most cases (>90%) are reported from the seven states with well-established foci of zoonotic transmission (Connecticut, Massachusetts, Minnesota, New Jersey, New York, Rhode Island, Wisconsin). In the Northeast, areas of high endemicity include islands off the southern coast of New England. On the mainland, babesiosis is highly endemic in southeastern Massachusetts, including Cape Cod, the coastal counties of western Rhode Island and eastern Connecticut, the counties east of the Hudson River in the Lower Hudson Valley (New York), and the south central counties of New Jersey. In the upper Midwest, babesiosis caused by B. microti is moderately endemic in Minnesota and Wisconsin ( Fig. 281.1 ).
Incidence and Prevalence
The incidence of babesiosis has steadily increased over the past 30 years. In New York State, the first state to mandate the reporting of babesiosis, more than 5800 cases have been notified to the health authorities. About 1100 cases were reported from 1986 to 2005, and more than 3500 cases in the following decade. The sharp increase noted between 2006 and 2015 resulted from the emergence of babesiosis in the Lower Hudson Valley combined with the maintenance of highly endemic foci on eastern Long Island. Along the northeastern seaboard, babesiosis has emerged in areas that were once at the periphery of the “historical heartland,” namely southern Maine and southern New Hampshire to the north and Pennsylvania, Delaware, and Maryland to the south. In the upper Midwest, the number of annual cases has risen steadily since 2005. A few cases have been reported in Illinois, Indiana, and Michigan. Babesiosis caused by B. microti remains an emerging infectious disease in the United States.
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 (7% among blood donors), Block Island (9% among residents), southern Connecticut (0.5%–9% among blood donors), Shelter Island (4% in blood donors; 4%–7% among residents), and eastern Long Island (16% among residents). In Minnesota, seroprevalence among blood donors has been reported at 2%. Given that seroprevalence is much higher than prevalence of clinical babesiosis, asymptomatic infection is more common than recognized or reported.
Modes of Transmission
Tick Bite
B. microti is primarily acquired during the blood meal of the tick I. scapularis, but only one-half of patients recall a tick bite in the 8 weeks prior to symptom onset. The nymphal stage, the primary vector, is most active from late spring to early summer (see “ Microbiology ” later). Because the latency period typically lasts from 1 to 4 weeks, one-fifth of cases are diagnosed in June, one-half in July, and another one-fifth in August. Some cases present as early as late spring. Patients who present in late summer or early fall likely acquired the infection from an adult female tick.
Blood Transfusion
B. microti can be transmitted via transfusion of blood components prepared from contaminated blood donated by asymptomatic carriers or symptomatic individuals who did not suspect the infection. Implicated blood donors typically have engaged in outdoor activities. Less than one-fifth have experienced fatigue or fever within 24 months prior to index donation. Even fewer (8%) have experienced chills. Consistent with the seasonality of tick-borne babesiosis, three-fourths of transfusion-transmitted babesiosis (TTB) cases are diagnosed from June through November, with one-fifth in August alone. Given that asymptomatic infection can persist in untreated individuals for longer than a year, TTB is diagnosed year-round. Most TTB cases (87%) occur in residents of highly endemic states (see earlier list). Outside endemic areas, TTB typically involves contaminated blood products that are imported from endemic areas or are derived from blood donations by individuals following their return from endemic areas.
More than 250 TTB cases caused by B. microti have been identified since the first case was reported in 1979; three-fourths have occurred since 2005. Most cases involve red blood cell (RBC) units. A few have been attributed to whole-blood–derived platelets contaminated with residual RBCs. At time of transfusion, the age of liquid-stored RBC units has ranged from 4 to 42 days; one platelet unit was 5 days old. In March 2018, when the US Food and Drug Administration (FDA) approved two tests for donor blood screening (see next paragraph), B. microti was still the pathogen most frequently implicated by investigations of transfusion-related illnesses. From fiscal year 2010 to fiscal year 2016, B. microti accounted for one-fourth of transfusion-related deaths caused by microbial infection.
Using an arrayed fluorescence immunoassay for detection of B. microti immunoglobulin G (IgG) and a real-time polymerase chain reaction (PCR) for detection of B. microti DNA, the risk posed by blood donations in some highly endemic areas (Massachusetts and Connecticut) has been carefully assessed. Among donations collected from June 2012 through September 2014, 0.3% reacted in one test or both. Three-quarters of the donations were positive for B. microti IgG but negative for B. microti DNA, whereas one-fifth were positive for both. Antibody-positive donations were obtained throughout the year. Consistent with the seasonality of tick-borne babesiosis, donations that were DNA positive but IgG negative were obtained from June through September. Among donors who tested positive for B. microti DNA at time of index donation, most (86%) were no longer infected a year later. The median time to parasite DNA clearance was 4.7 months. Among those who tested positive for B. microti IgG, only 8% had seroreverted a year later. The median time to seroreversion was 17.1 months. None of the 75,000+ donations screened with the two FDA-approved tests were implicated in a TTB case. In contrast, 1 in 18,000 unscreened donations obtained from the same area was implicated in a TTB case. When five highly endemic states (Connecticut, Massachusetts, Minnesota, New Jersey, New York) were analyzed along with two states that recently emerged as endemic (Maine and New Hampshire), the risk for TTB was estimated at 1 case per 100,000 donations for the period from January 1, 2010 to August 31, 2016.
Transplacental Passage
Unequivocal evidence of transplacental transmission came from a case reported in 2012. A splenectomized mother was admitted after a 10-day history of fever and rigors. Intraerythrocytic B. microti ring forms were identified on a blood smear and in the amniotic fluid. On the second day of hospitalization, the mother underwent cesarean section. Immediately after delivery, blood was obtained from the neonate and intraerythrocytic parasites were noted on a thin blood film.
Probable congenital babesiosis has been reported for at least nine other cases. For seven cases, mothers were asymptomatic throughout pregnancy. In one such case, B. microti likely was acquired during the first trimester of pregnancy. Two symptomatic mothers received a diagnosis of Lyme disease during the last trimester of pregnancy, but B. microti infection was not suspected. Symptoms of babesiosis developed in the neonates during the third to the sixth week of life and often consisted of fever accompanied by pallor. Laboratory tests revealed hemolytic anemia, thrombocytopenia, and neutropenia. In all cases but one, anemia was so severe that a blood transfusion was required. At diagnosis, parasitemia ranged from 2% to 40%. When tested for B. microti antibody, neonates and their mothers were seropositive. One neonate who presented with tachycardia and respiratory distress required an exchange transfusion, which was performed manually. This neonate had a twin who was seropositive for B. microti but remained healthy. In another case, B. microti antibody was detected in a heel stick blood sample obtained on the third day of life, raising the possibility that maternal IgG directed against B. microti protects newborns from congenital babesiosis very early in life. In addition to vertical transmission, babesiosis has been diagnosed in neonates following blood transfusion.
Solid Organ Transplantation
Two cases of transplantation-associated babesiosis have been described. Both men had received a kidney allograft obtained from the same deceased donor and began experiencing symptoms 5 weeks posttransplantation. The diagnosis of babesiosis was made 8 weeks posttransplantation. Despite immunosuppressive therapy, both men tested seropositive for B. microti. Pretransplantation serum samples did not react with B. microti antigen, an observation consistent with the denial by these allograft recipients of tick exposure and blood transfusion prior to transplantation. The organ donor, however, had received multiple blood transfusions, including one from a blood donor who tested positive for B. microti antibody during the retrospective investigation. It is presumed that some B. microti parasites from the blood donor had remained in the vasculature/fluids of the renal allografts at time of transplantation. In support of this explanation, corneas from the deceased organ donor were transplanted but neither recipient presented clinical or serologic evidence of B. microti infection.
Risk Factors
Babesiosis caused by B. microti often is severe in individuals with one or several of the following risk factors: asplenia, X-linked agammaglobulinemia, malignancy, low CD4 + T-cell counts associated with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), blockade of tumor necrosis factor-α (TNF-α) for chronic inflammatory disorders such as inflammatory bowel disease, and immunosuppressive therapy for transplantation, B-cell lymphoma, or an autoimmune disorder. These risk factors also pertain to the transmission of B. microti by blood transfusion. In this setting, given that most cases have 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 anemia of prematurity. Two-thirds of TTB patients are older than age 50 years, but two-thirds of those younger than age 40 years have a hereditary RBC disorder.
United States: Other Babesia Species
Babesia duncani and B. duncani –type organisms are the etiologic agents of human babesiosis along the Pacific Coast. The index case (WA1) occurred in a 41-year-old normosplenic man from a forested area of south central Washington State. The four cases in California (CA1–CA4) developed in splenectomized men in their 20s to 40s who lived or had outdoor exposure in areas ranging from Sonoma County to San Bernardino County. 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. The second case was diagnosed in a premature male infant who had received two blood transfusions. The implicated donor lived in the San Francisco Bay area and had vacationed in a rural area of central Oregon 3 months prior to donating. The third case involved a 59-year-old patient who had sickle cell disease. The 67-year-old donor reported a possible tick bite during a hike in the San Francisco Bay area. The winter tick Dermacentor albipictus presumably is the vector for transmission of B. duncani . The prevalence of B. duncani infection remains unclear because clinical cases have been too few to validate the serologic test.
B. divergens –like organisms have caused disease in Arkansas, Kentucky, Michigan, Missouri, and Washington State. All six patients were older than 50 years of age, and asplenic. In one case, transfusion is the suspected mode of transmission. The patient lived in Arkansas but blood donated in Missouri was the likely culprit, thereby bringing to three the number of B. divergens –like infections that originated in Missouri. Isolates from the five cases that originated in the Midwest 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. In Tennessee, three cases were uncovered by querying claims data from a managed care organization. One such case may have been caused by a B. divergens –like organism.
Europe: Babesia divergens
Approximately 40 cases of babesiosis have been attributed to B. divergens, a parasite of cattle that is transmitted by Ixodes ricinus. Most cases occurred in France and Ireland, particularly in regions with extensive cattle farming. Isolated cases have been reported from Portugal, Spain, Norway, Sweden, Finland, Georgia (ex-USSR), Turkey, and Croatia (including the index case). Nearly all patients experienced a severe illness and had been splenectomized, although one had a rudimentary spleen and another had functional hyposplenism caused by celiac disease. TTB caused by B. divergens has not been reported from Europe, although asymptomatic B. divergens infection is not uncommon, as indicated by seroprevalence in Slovenia (4.1% of forestry workers), western Austria (2.1% of blood donors), midwestern Germany (4.2% of individuals with clinical or serologic evidence of Lyme borreliosis), and southern Sweden (7.0% of individuals seropositive for Borrelia burgdorferi s.l.).
Europe: Other Babesia Species
Cases of B. venatorum infection have been reported in Italy, Austria, Germany, and Sweden. The five patients were splenectomized men older than 50 years of age. Roe deer are a reservoir host for B. venatorum in Europe, and the bite of an I. ricinus tick is the suspected mode of transmission. The prevalence of asymptomatic infection remains unknown because B. venatorum sera cross-react with B. divergens antigen. Attributed to B. divergens based on morphology and seroreactivity, some early cases of babesiosis in Europe may have been caused by B. venatorum.
The first case of B. microti infection native to Europe was reported in 2007 from Germany. A 42-year-old woman presented with fever and chest pain 1 week after chemotherapy for acute myeloid leukemia. Intraerythrocytic parasites were observed on Giemsa-stained blood smears and identified as US-type B. microti. The platelet concentrate transfused 6 days before the diagnosis of babesiosis had been prepared from blood donated by an individual who subsequently tested seropositive for B. microti. Additional cases were reported in 2016 from northeastern Poland. All six patients were immunocompetent and had been bitten by a tick within 8 weeks prior to presentation. No parasites were seen on blood smear, but a fragment of the B. microti 18S ribosomal RNA (rRNA) gene was amplified and sequenced, establishing for the first time that B. microti organisms of the Munich lineage can cause disease in humans. Cases of travel-associated babesiosis have been reported throughout Europe and explained by a recent stay in the northeastern United States. Asymptomatic B. microti infection is prevalent in residents of rural, forested areas across Europe as indicated by serosurveys conducted in northeastern Poland (4.4% of foresters), eastern Switzerland (1.3% of blood donors), midwestern Germany (8.3% of individuals with clinical or serologic evidence of Lyme borreliosis), eastern France (2.% of foresters who are seropositive for other tick-borne pathogens), and Belgium (9% of patients presenting within 1 month after a tick bite).
Asia: Babesia venatorum
The first case of B. venatorum infection in Asia was documented in northwestern China. A series of 48 cases was subsequently reported from northeastern China. All 48 cases reported a tick bite within 2 months prior to seeking medical care; none had received a blood transfusion within 2 years. All had a spleen, but only one-third were older than 50 years. A survey of ticks revealed that the taiga tick Ixodes persulcatus is the likely vector for B. venatorum in northeastern China.
Asia: Other Babesia Species
The first two cases of B. microti infection in Asia were documented in Taiwan. A case of TTB was subsequently reported from Kobe, Japan. The isolate has defined the Kobe lineage, one of the four lineages within the B. microti species complex. The asymptomatic blood donor resided on the nearby Awaji Island, where the field mouse Apodemus speciosus was identified as a reservoir host for Kobe-type organisms. The vector is unknown. B. microti organisms of the Hobetsu lineage are found in A. speciosus mice throughout Japan, and can be transmitted by Ixodes ovatus ticks. Hobetsu-type organisms have infected humans, as revealed by a serosurvey, but no cases of babesiosis have been reported. In mainland China, B. microti has caused disease in the southern provinces, particularly in Yunnan along the border with Myanmar. At least two cases were caused by US-type organisms. One case was coinfected with Plasmodium falciparum and another with Plasmodium vivax.
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. A series of 31 cases caused by Babesia crassa, a species found in sheep, has been documented in northeastern China. All cases were mild to moderate; none were asplenic.
Rest of the World
A case of US-type B. microti has been documented in Australia. On the American continent, a case of B. microti infection was identified in Manitoba, Canada, whereas three cases were diagnosed on the Yucatan peninsula, Mexico. Asymptomatic B. microti infection has been documented in Bolivia and Brazil. Cases caused by Babesia spp. that infect cattle ( B. bigemina , B. bovis ) have been reported from Colombia . Asymptomatic infections with these two Babesia spp. have been reported from Brazil, Colombia, and Cuba. On the African continent, three cases have been reported from Egypt, of which one was acquired from a pet dog. A case of B. divergens –like infection was diagnosed in a splenectomized resident of the Canary Islands. In South Africa, babesiosis was diagnosed in two patients upon their return from Namibia and Zimbabwe. Isolated cases of B. bovis infection, of which two were fatal, have been documented in Mozambique.
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