Any discussion of transfusion-transmitted pathogenic agents must first consider the parameters used to define cases of transmission. A useful starting point is to consider fundamental requirements for the transmission of a pathogenic agent from a blood donor to a blood recipient that are analogous to Koch's postulates. First, the agent must establish a viable infection in the blood donor. Second, and critical to transmission, the agent must be present and/or circulate in the peripheral blood of the donor. Third, the agent must survive the blood collection process and remain viable under normal blood storage conditions. Last, the agent must be able to infect the blood recipient following blood transfusion. When all four of these requirements are met, as they are for Babesia spp., transfusion transmission can and does occur. As discussed above, Babesia spp. can infect blood donors and is found in the peripheral blood (i.e., intraerythrocytic). The following discussion serves to address the remaining two requirements needed to establish transfusion transmission.
The first case of TTB is often ascribed to a 1968 report from Ireland that purportedly identified the transmission of B. divergens
to a 48-year-old asplenic male approximately 4 months after receiving a blood transfusion (31
). However, a follow-up report by those same authors attributed this patient's infection with B. divergens
to a caravan holiday in County Galloway, Ireland, during mid-August (32
). Lending further credence to the natural acquisition of infection, three cases of “red water” (babesiosis) were reported in cattle from the same area of County Galloway that August.
Therefore, it appears that the first case of TTB was reported in 1980 from Boston, MA, and involved the transmission of B. microti
to a 70-year-old patient after the transfusion of 20 platelet units (60
). The implicated donor was a summer resident of Nantucket Island who was asymptomatic at the time of blood transfusion. Since that initial report, TTB has been reported with increasing frequency, and current estimates suggest that between 70 and 100 cases have occurred (41
). Determining an accurate estimate is difficult, since many cases of TTB have not been reported in an organized way or were not novel enough to warrant consideration for publication (76
). More recently, the advent of hemovigilance and governmental reporting systems has allowed more-accurate estimates of current TTB cases. Based on recent data collected over 3 years, the frequency of cases has increased dramatically, with 18 cases reported by the American Red Cross during 2005 to 2007, six cases from Rhode Island in 2007, seven cases in New York City during late 2008, and an extensive review of cases by the FDA from 1997 to 2007 (41
). Of particular note and concern, at least 12 fatalities associated with TTB have been reported, 8 of which occurred in the last 4 years.
All reports of TTB cases in the United States have implicated B. microti
, with the exception of two transmission cases linked to B. duncani
(formerly known as WA-1) that occurred on the West Coast (Table ) (48
). The index B. duncani
case occurred in a 76-year-old patient, while the implicated donor resided in Washington State and was generally healthy, although he reported intermittent fatigue. Testing of residual samples from the implicated donation revealed a B. duncani
titer of 1:65,536, and parasitemia was subsequently confirmed by hamster inoculation. The second B. duncani
transfusion case was reported from California in a premature infant. The implicated donor was a resident of the San Francisco Bay area, who may have become infected on an outdoor recreational trip. As in the previous report, the implicated donor demonstrated an extremely high B. duncani
titer, 1:40,960, 2 months after the implicated donation and was demonstrably parasitemic based on xenodiagnosis by hamster inoculation. It is unclear if high IFA titers are common for B. duncani
infections or if this reflects a peculiarity of this IFA assay, which does not cross-react with B. microti
. A third, as-yet-unpublished B. duncani
transmission case reportedly occurred during 2009 in California, but specifics of this case are not yet available. With our current limited understanding of B. duncani
's distribution and frequency in blood donors, hospitals and blood transfusion centers on the West Coast need to remain alert to the potential transfusion transmission of this agent.
Outside North America, an autochthonous case of TTB from Japan that involved a B. microti
-like species of the parasite was reported (84
). The only other reported transfusion case outside North America was a 2007 autochthonous case from Germany that involved B. microti
(Table ) (51
). Although only a single donor demonstrating borderline (IgG titer, 1:32) reactivity to B. microti
was identifiable, alternative routes of infection in the recipient proved unlikely. In all likelihood, other cases of TTB have occurred outside the United States, but given the general lack of parasite and disease recognition in many areas of the world, one can reasonably infer that transfusion cases outside the United States routinely go undetected.
Clinical features of TTB cases are generally thought to parallel those observed for naturally acquired infections. Incubation times for TTB cases generally mimic what is seen for natural infections; infections usually take 1 to 9 weeks to become apparent. Factors influencing the incubation period are the immune status of the patient, the parasite species and/or strain implicated in transmission, and, although not well defined, infectious dose. Occasionally longer incubation periods have been reported, particularly among patients with sickle cell anemia (4
For those TTB cases where a specific blood component has been implicated, the vast majority of cases have identified a unit of packed red blood cells (RBCs) as the source of Babesia
). Several transmission cases, however, have also implicated platelet products derived from whole blood, which presumably contains either contaminating red cells infected with the parasite or extracellular B. microti
. In contrast, apheresis platelets have not been implicated in a transfusion case, perhaps since they contain few, if any, contaminating red blood cells. However, the potential for extracellular parasites of Babesia
suggests that any blood product not frozen may pose a risk of transmitting infection (94
As observed for the general population, blood recipients at greatest risk for becoming infected with B. microti
are infants, the elderly, patients without spleens, and those who are immunocompromised. The fact that most blood recipients have underlying health-related issues and tend to be older (i.e., >50 years of age) increases their risk for developing babesiosis following transfusion with a Babesia
-infected unit. It has also become apparent that sickle cell patients, who are functionally asplenic, are also at an increased risk for infection with Babesia
). However, the primary patient group at risk is the elderly. Previous reports suggested that severe clinical disease and chronic infections are most often observed for healthy patients ≥50 years old (71
), a phenomenon reported to be unrelated to an increased risk for the acquisition of natural infections (73
). Among blood recipients, a recent report of TTB by the American Red Cross revealed that 13 of 18 (68%) reported cases between 2005 and 2007 involved recipients between the ages of 61 and 84 years old. One explanation for the greater number of cases in elderly patients may be an age-associated decline in resistance to B. microti
). Studies in mice have revealed that resistance to infection with B. microti
is conferred by the adaptive immune system, which is genetically determined and associated with age.
Cases of TTB are increasingly being reported outside of areas where Babesia
is normally thought to be endemic. In areas where the disease is not endemic, transmission occurs primarily via two mechanisms. In the first scenario, a blood donor from an area where the parasite is not endemic travels to and becomes infected in an area where Babesia
is endemic. For example, a transfusion-transmitted case was reported in Canada (where Babesia
spp. are not endemic), but the implicated donor likely acquired B. microti
infection during travel to Cape Cod, MA (63
). This case also provides instructive lessons on follow-up investigations, as the implicated unit of red cells was collected in February, well outside the known tick season and 6 months after the presumed naturally acquired infection. The donor was asymptomatic but upon follow-up was demonstrably parasitemic by PCR and serologically positive, with a titer of 1:1,024. A similar case occurred in Texas, where a 57-year-old male was identified as having babesial infection 7 weeks posttransfusion (20
). The recipient subsequently died due to gastrointestinal hemorrhage with Babesia
-induced hemolysis identified as a probable complication factor. The implicated donor, identified as being positive by IFA testing and PCR, likely became infected 3 to 5 months earlier while summering in Cape Cod, MA.
Alternatively, recipients in areas where the parasite is not endemic may become infected following the transfusion of blood products imported from an area where Babesia
is endemic. A recently reported case highlighted the infection of a California resident who received a transfusion of blood products (January 2007) from a donor residing in Maine (92
). Reports of clinical babesiosis in Maine are rare (83
), but the donor resided in coastal Southern Maine, from which most cases are reported, and the donor's titer was 1:256 approximately 2 months after the implicated donation. The donor acknowledged that he frequented tick-infested areas and may have become infected in late August 2006, when he sought treatment for fever, chills, weight loss, and fatigue—classical symptoms of babesiosis.
With multiple reports of TTB in the last 5 years, it is clear that the number of cases is on the rise, particularly for U.S. cases associated with B. microti
. The reason for this rise is not readily apparent, but several factors likely contribute to the apparent increase in TTB case frequency. First, recipients of blood transfusions increasingly represent an aged and immunocompromised population, since increasing marrow and solid-organ transplants are performed each year (128
). Second, education efforts and published case reports have raised the awareness of TTB, leading to an increased recognition of cases by physicians and hospital transfusion services. Last, and perhaps more importantly, the geographic range of the parasite is expanding, albeit slowly, beyond its historical foci in areas of Southeastern New England that encompass portions of Connecticut, Massachusetts, Rhode Island, and nearby offshore islands where the parasite is highly endemic. Recent serosurveys and clinical case reports suggest a wider distribution, including large portions of Connecticut and New Jersey, the Hudson River Valley, and coastal Maine (26
Estimates of transfusion risk associated with B. microti
are limited and vary considerably. A recent report from Rhode Island suggested the mean rate of TTB to be approximately 1 case per 15,000 units of RBCs transfused (4
). Estimates from Connecticut ranged from earlier estimates of 1 case per 601 units of transfused RBCs (36
) to later estimates of 1 case per 1,800 to 1 case per 100,000 red cell units transfused (5
). In most instances, the rate of transmission is likely underestimated due to an ongoing failure to recognize true cases of transmission. With the implementation of a national hemovigilance program in the United States, under the auspices of the National Healthcare Safety Network administered by the CDC, more-accurate estimates of adverse transfusion events and transfusion risk associated with B. microti
should be forthcoming.