EDITORIAL: The problem of transfusion‐transmitted babesiosis

Babesiosis is an emerging infectious disease caused by intraerythrocytic protozoa with clinical features similar to those of malaria.1,2 It usually is transmitted by hard-bodied (Ixodid) ticks but can also be transmitted through blood transfusion.3-8Babesia microti, the most common Babesia species that causes human babesiosis, is the most frequently reported transfusion-transmitted microbial agent in the United States.8 More than 70 transfusion-transmitted cases have been described since the initial report in 1980 with a significant associated morbidity and mortality.3-7 Whole blood, red blood cells (RBCs), and platelets (PLTs) have been implicated, although only one case of transfusion-transmitted babesiosis (TTB) has been associated with PLT transfusion.3-7 The more recently discovered Babesia duncani species also can be transmitted through blood transfusion.9,10 Unlike tick transmission, TTB may occur at any time of the year and anywhere in the United States because of asymptomatic infection in donors who may reside in or travel to endemic areas and because of interregional shipment of blood components.3-7 The current issue of TRANSFUSION has five papers that focus on the important developing problem of TTB. Babesiosis is named in honor of Viktor Babes, a Hungarian pathologist who first described Babesia from the blood smears of febrile cattle in 1888.11 The first human case of babesiosis was reported in 1957 in Yugoslavia and the first confirmed US case was described on Nantucket in 1968.12,13 Over the past 30 years, the epidemiology of the disease has changed from a few isolated cases to the establishment of endemic areas with a progressively increasing number of Babesia infections in southern New England, New York, and the northern Midwest and reports from a wide geographic range in North America, Europe, Asia, Africa, and South America.1,2 The health burden of TTB is significant, as measured both by frequency and by severity of illness. Although babesiosis is the most commonly reported cause of transfusion-transmitted infection at the present time in the United States, an accurate determination of incidence is problematic because most cases are thought to go unreported.5-7,14 Many physicians and the general public are unfamiliar with babesiosis, even in endemic regions. The symptoms of acute Babesia infection are nonspecific (fever, chills, headache, sweats, myalgias) and approximately one-quarter of such infections in adults are asymptomatic.14 Accurate estimates of TTB incidence are further complicated by the lack of a standard case definition and difficulty in definitively establishing a case. Confirmation of a definite case can be made if a blood recipient has typical clinical manifestations and laboratory diagnosis of active Babesia infection with no possibility of tick transmission, has received a blood transfusion within the previous 3 months, and there is laboratory confirmation of active Babesia infection in at least one blood donor of the transfused product. To further complicate incidence estimates of TTB, risk varies according to the location of donor populations. The geographic distribution of babesiosis is not uniform even within endemic regions, as illustrated by the American Red Cross Connecticut seroprevalence study reported in this current issue of TRANSFUSION.15,16 These problems help account for the large variation in estimates of TTB risk. The risk of acquiring babesiosis from transfused blood between 2005 and 2007 differed approximately 50- to a 100-fold between the American Red Cross Hemovigilance Program (1 case per 994,444 RBC units), the Rhode Island Blood Center Program (1 case per 20,454 RBC units), and the Rhode Island/Brown University study (1 case per 8532 RBC units).17-19 A much higher rate (1 case per 604 RBC units) was derived from a small active surveillance study in Connecticut.4 Many TTB cases are severe and these occur almost exclusively in immunocompromised patients.1,3,17,20 Approximately one-third of the cases reported by the American Red Cross Hemovigilance Program were fatal and occurred in people who had existing medical conditions that increased their susceptibility to severe infection.17 Those known to be predisposed to severe babesiosis include newborn infants or people over age 50; people who lack a spleen; people who suffer from malignancy, HIV, or hemoglobinopathy; or people who are taking immunosuppressive drugs. They do not always respond to standard therapy with atovaquone and azithromycin or clindamycin and quinine.21 What can be done to ameliorate the problem of TTB? Preventive options that have been considered include geographic and seasonal exclusion of donors in areas known to be hyperendemic, educating donors about babesiosis, and precluding any from donating if they report ever having had babesiosis, laboratory screening of blood donors to prevent those who are Babesia infected from donating blood, especially to selective patient populations that are at higher risk for severe disease, and inactivation of Babesia in donated blood.19 Several of these strategies are unlikely to be very effective. Geographic and seasonal exclusion of donors will fail to prevent all cases of TTB and will unnecessarily eliminate donations from a large number of uninfected donors.15 Although no one has formally assessed the efficacy of the current approach of questioning donors about babesiosis and preventing any who report having had the disease from ever donating again, it clearly is not sufficiently effective because the annual number of TTB cases is substantive and continues to increase. This strategy also has the disadvantage of precluding blood donations from people who were incorrectly diagnosed as having had babesiosis or who experienced babesiosis in the distant past and are no longer infected. Although Babesia parasitemia may persist for as long as 2 years, infection subsequently clears.22 There is no current evidence that Babesia infection can persist indefinitely, even in untreated patients. The most promising strategies to prevent Babesia transfusion include screening of blood donors by laboratory testing and pathogen reduction technology. At a time when securing an adequate number of donations is a problem, whatever laboratory screening method is used should balance the need to identify as many infected donors as possible and at the same time avoid excluding uninfected people from blood donation. Nucleic acid amplification test technologies (NAT), including polymerase chain reaction (PCR) and such isothermic methods as transcription-mediated amplification, are attractive screening methods because they are highly specific and sensitive.23 Quantitative PCR can detect as few as one to five malaria-parasitized RBCs/5 × 106 RBCs/µL.24 Data from our laboratory indicate a similar or even better sensitivity for Babesia quantitative PCR. This translates to detection of as few as five Babesia-infected erythrocytes in a milliliter of blood (0.0000001% parasitemia or 2500 Babesia parasites in a unit of blood). Whether this sensitivity will be sufficient to detect all infected donors is unclear because the minimum concentration of Babesia parasites necessary for transfusion transmission is unknown. The possibility of misidentifying people as infected because of amplicon contamination or the presence of “dead DNA” in previously infected people can be minimized by maintaining high-quality laboratory standards and asking about recent Babesia infection. Testing for Babesia antibody is another highly sensitive and specific screening approach, although antibodies are undetectable early in the course of infection and can persist for at least 9 months after Babesia infection has cleared.22 Use of a specific cutoff titer that is associated with active infection could effectively identify infected donors and prevent the exclusion of prospective donors who are uninfected but have persistent antibody. Babesia IFA titers of 1:1024 or more have been associated with active infection.25 Use of blood smear or injection of laboratory animals is less useful because they are either insufficiently sensitive, time-consuming, or too costly. No laboratory donor screening program is yet operational but one is in development at the Rhode Island Blood Center in collaboration with Imugen, Inc., that limits screened blood to high-risk populations more likely to suffer severe disease.19 Such laboratory screening approaches require review by the Food and Drug Administration (FDA) that is responsible for all investigational new drug protocols for unlicensed tests. Treatment of blood products to kill potential pathogens may be the most effective approach for prevention of TTB. Plateletpheresis-associated Babesia transmission can be prevented with the use of Mirasol PRT in an animal model.26 Although apheresis PLTs have never been shown to cause TTB, this approach and other methods of destruction of Babesia in RBC products need to be developed and evaluated. It also will be important to determine whether pathogen reduction is more cost-effective than donor screening procedures, especially at a time when high medical costs are a nationally recognized problem. It is possible that a combination of methods will be most effective. Pathogen reduction might be used in areas with the highest indigenous Babesia incidence and laboratory screening of donor blood in other endemic areas. Significant progress has been made in protecting the blood supply, but much additional work needs to be done. The problem has drawn increased attention from blood centers and hospitals. More studies are being conducted to better understand the problem. The proceedings of a recent FDA workshop on TTB are published in this issue of TRANSFUSION and they review the biology, epidemiology, pathogenesis, and prevention of TTB.19 Presentations included an overview of Babesia species that infect people, blood transfusion transmission of non–B. microti species, the FDA reporting mechanism for documentation of TTB, a laboratory blood donor screening program being developed to reduce TTB at the Rhode Island Blood Center, additional proposed laboratory blood screening and donor reentry strategies, protozoa inactivation methods being developed by Cerus and CaridianBCT Biotechnologies Corporations, and other related topics. This meeting was important in helping to better define and highlight the significant and growing problem of TTB and to review preventive methods. Further scientific studies to determine the optimal strategies for prevention, funding to support such studies, and implementation of programs to reduce TTB are urgently needed. The authors are engaged in scientific collaborations with some of the authors of the papers that appear in this issue of TRANSFUSION but have no other significant conflicts of interest.