Transfusion-associated babesiosis after heart transplant. (Dispatches).

We describe a 54-year-old spleen-intact man with transfusion-associated Babesia microti infection after a heart transplant. Adult respiratory distress syndrome developed in the patient, and he required mechanical ventilation. Our experiences with this patient suggest that babesiosis should be considered in the differential diagnosis of transplant patients who have fever and hemolytic anemia.

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Babesiosis is a tick-borne protozoan illness caused by infection of erythrocytes with various species in the genus Babesia. In the United States, Babesia microti is the agent most commonly reported to cause human infection (1). More recently, the MOl-type, WA 1-type, and CA 1-type Babesia species have been identified as causing clinical disease in the United States (2-5). Babesia infection can also be acquired by blood transfusion (2,6,7). More than 40 cases of transfusion-transmitted B. microti infection have been reported in the United States (R. Cable and B. Herwaldt, unpub, data). B. microti infection is often asymptomatic (8) but may cause a malaria-like illness characterized by fever and hemolytic anemia. Babesiosis can also be associated with severe complications that include renal failure (9,10), disseminated intravascular coagulation (9), and adult respiratory distress syndrome (1,9,10). The risk of developing this clinical infection is increased for elderly, asplenic, or immunosuppressed patients (11). Here we describe a case of B. microti infection in a 54-year-old spleen-intact man acquired by blood transfusion after cardiac transplantation.

Case Report of Blood Recipient

The patient, a 54-year-old resident of New Jersey, had a medical history of coronary artery disease and atrial fibrillation. Approximately 18 months before his transplant, a "bull's-eye" rash developed, and the patient was empirically treated for Lyme disease. He did not recall a tick bite.

On August 19, 2000, he had an anterior wall myocardial infarction and was hospitalized in his hometown. He required intubation, placement of a coronary stent and an intra-aortic balloon pump, use of intravenous cardiac inotropes, and transfusion of 2 U of packed red blood cells (PRBC). When fever developed, he was empirically treated with vancomycin, ciprofloxacin, and metronidazole without improvement. No source of infection was found. On September 6, he was transferred to a New York City medical facility for placement of a left ventricular assist device. Staphylococcus epidermidis was isolated from two sets of blood cultures. He was then treated with vancomycin and trimethoprim-sulfamethoxazole for 4 weeks.

On September 26, the patient received an orthotopic cardiac transplant. He received 32 U of irradiated leukocyte-reduced PRBC, 23 U of fresh frozen plasma (FFP), 6 U of irradiated platelets, and 4 U of cryoprecipitate during his 5.5-week hospital stay. On October 16, he was discharged on an immunosuppression regimen of cyclosporine, mycophenolate, and prednisone.

On November 5, the patient became febrile. He was evaluated by his cardiologist 3 days later. He had fever, chills, diaphoresis, headache, and sore throat. Blood and throat cultures were obtained, as well as an endomyocardial biopsy specimen. No source of infection or evidence of cardiac rejection was found.

On November 9, he was hospitalized again for evaluation of continued fever. On admission, his temperature was 38.4xC. His surgical wound had healed well. Laboratory tests showed a leukocyte count of 4.3 x [10.sup.3]/[mm.sup.3] (83% neutrophils, 9% lymphocytes, 8% monocytes), hemoglobin concentration of 11.4 g/dL, and a platelet count of 54,000/[mm.sup.3]. On November 10, the staff of the hospital parasitology laboratory identified intraerythrocytic ring forms and tetrads consistent with B. microti infection on a peripheral blood smear; these results were confirmed by the Centers for Disease Control and Prevention (CDC). The parasitemia level was 1.6%. Indirect fluorescent antibody (IFA) testing (12) of his serum at CDC showed that his IFA titers had risen from [less than or equal to] 1:8 (i.e., negative) pretransplant to 1:1024 posttransplant (Table). Nested polymerase chain reaction (PCR) analysis of blood, using primers described previously (13), was positive for B. microti DNA. Results of pre- and posttransplant serologic testing for antibodies to Borrelia burgdorferi, Ehrlichia chaffeensis, and the agent of human granulocytic ehrlichiosis (14), performed at the New York State Department of Health, were negative (Table).

On November 10, therapy with quinine (650 mg orally, 3 times a day) and clindamycin (400 mg intravenously, 4 times a day) was begun. His course was complicated by worsening parasitemia (maximum documented level was 3.1% on November 13), hemolytic anemia (hemoglobin concentration decreased from 11.4 g/dL on November 9 to a minimum value of 7.4 g/dL on November 15), acute renal failure (creatinine value rose from 1.4 mg/dL on November 9 to a maximum level of 3.3 mg/dL on November 15), and adult respiratory distress syndrome requiring mechanical ventilation.

On November 14, his therapy for babesiosis was changed to azithromycin (500 mg intravenously, once a day) and atovaquone (750 mg orally, 2 times a day) because of severe tinnitus, increased level of parasitemia (3.1% on November 13), and ongoing fever (maximum of 38.6[degrees]C). On November 21, he was afebrile and had a negative blood smear. He was discharged on November 25. Therapy with azithromycin (250 mg orally, once a day) and atovaquone (750 mg orally, 2 times a day) was continued for a total of 2 weeks on these drugs. The patient remained well as of August 2001.

Investigation of Blood Donors

We traced the donors of the 32 PRBC units transfused during the patient's hospitalization in New York City. For two donors, the transfused units had associated frozen components (i.e., FFP) available that could be retrieved; for six donors, PRBC units from subsequent donations were available for testing. The blood products from these eight donors were negative for antibodies to B. microti by IFA testing.

The other 24 donors submitted blood for testing. On March 12, 2001, the New York State Department of Health laboratory reported that one donor had an IFA titer of 1:256, which was confirmed by CDC (Table). The other 23 donors had negative IFA titers. The blood specimen from the implicated donor had been obtained on February 28, 2001, 5 months after the original blood donation on September 22, 2000. The PRBC unit was transfused on October 1, 2000, and the patient first reported fever on November 5, 2000. Thus, the incubation period for the case of babesiosis was estimated to be 35 days. CDC performed additional diagnostic testing on the implicated donor's blood. PCR analysis was negative for B. microti DNA, and parasitemia did not develop in hamsters injected with his blood (Table). The donor was thus implicated on the basis of serologic rather than parasitologic data. Given that he was not treated for babesiosis, the negative results of the parasitologic testing suggest that the donor's infection cleared spontaneously. However, he could have had low-level or intermittent parasitemia not detected by the parasitologic testing.

After the donor was implicated, other components from the index donation were investigated. No other patients received blood components from the implicated donation. The only other component identified was one unused unit of FFP, which already had been destroyed. The donor's only previous donation was 1 year before the index donation. The lone recipient from that donation remained asymptomatic but was not tested for evidence of B. microti infection.

Investigation of Implicated Donor

The implicated donor, a 45-year-old spleen-intact man from Westchester County, New York, had been asymptomatic the year before his blood donation. In 2000, he had visited New Haven County, Connecticut, in May; Long Island (Jones Beach), New York, in July and August; and Narragansett, Rhode Island, in July. He worked outdoors and gardened as a hobby. He did not recall a tick bite.

Investigation of Heart Donor

The heart donor was a 54-year-old woman who died after a cerebrovascular accident. She had lived and worked in New York City and had had no symptoms consistent with babesiosis before the stroke. While hospitalized, she had remained afebrile with a normal complete blood count and renal function. No serum from her was available for B. microti IFA testing.

Conclusions

We conclude that our patient, who lived in New Jersey, acquired babesiosis through transfusion of PRBC in New York City after a cardiac transplant. The evidence consistent with this conclusion includes the following: he did not recall a tick bite (most patients with babesiosis do not [9-11]); he did not spend much time outdoors; he was seronegative by B. microti IFA 5 days before his heart transplant and markedly seropositive when babesiosis was diagnosed 45 days after his transplant; he received blood from a donor with a B. microti IFA titer of 1:256; and he became symptomatic during the typical two 8-week incubation periods for transfusion-transmitted B. microti infection (7).

Other possible modes of transmission seem much less likely. We doubt he became infected through a blood transfusion in New Jersey; he was seronegative by B. microti IFA 4.5 weeks after the New Jersey transfusions. We also doubt that he acquired his infection while recuperating after his heart transplant; his limited outdoor activities made tick exposure unlikely.

More than 40 cases of transfusion-transmitted babesiosis have been reported in the United States. Most infections have been acquired through PRBC transfusions, but cases have also resulted from transfusion of frozen-deglycerolized red cell units (15,16) and platelet units (6,7) (the latter have residual red cells). Two previous cases of B. microti infection have been reported in solid-organ transplant patients, although no cases acquired through transplantation per se have been reported (17,18).

We initially treated our patient with quinine and clindamycin but later changed the regimen to atovaquone and azithromycin. A recent clinical trial demonstrated that the combination of atovaquone and azithromycin is as effective as quinine and clindamycin for the treatment of babesiosis in patients without life-threatening disease (such patients were excluded from this trial) (19). In our patient, who was critically ill, immunosuppressed, and a solid-organ transplant recipient, the combination of atovaquone and azithromycin was effective therapy.

Babesiosis should be considered in the differential diagnosis of transplant patients who have fever and hemolytic anemia, and blood transfusion should be considered as one of the possible means of acquisition of infection. Solid-organ transplant recipients may receive many blood products, which necessitates an extensive investigation to implicate a donor.

Table. Results of serologic testing, polymerase chain reaction
analyses, and hamster injection for specimens from the case-patient
with babesiosis and the implicated blood donor (a)

Date of specimen           Timing of specimen

Case-patient

September 21,2000            Pretransplant
November 14, 2000            Posttransplant
November 14, 2000            Posttransplant
September 21, 2000           Pretransplant
November 14, 000             Posttransplant
September 21, 2000           Pretransplant
November 14, 2000            Posttransplant
September 21, 2000           Pretransplant
November 14, 2000            Posttransplant
September 21,2000            Pretransplant
November 14,2000             Posttransplant

Implicated blood donor
(tested approximately
5 months after donation)

February 28, 2001             Postdonation
February 28, 2001             Postdonation
February 28, 2001             Postdonation

Date of specimen                     Test

Case-patient

September 21,2000             Babesia microti IFA
November 14, 2000               B. microti IFA
November 14, 2000               B. microti PCR
September 21, 2000            Agent of HGE, IgM (c)
November 14, 000               Agent of HGE, IgM
September 21, 2000             Agent of HGE, IgG
November 14, 2000              Agent of HGE, IgG
September 21, 2000         Ehrlichia chaffeensis IFA
November 14, 2000             E. chaffeensis IFA
September 21,2000                  Lyme ELFA
November 14,2000                   Lyme ELFA

Implicated blood donor
(tested approximately
5 months after donation)

February 28, 2001             Babesia microti IFA
February 28, 2001               B. microti PCR
February 28, 2001           Hamster inoculation (d)

Date of specimen                  Result of testing

Case-patient

September 21,2000          [less than or equal to] 1:8 (b)
November 14, 2000                       1:1024
November 14, 2000                      Positive
September 21, 2000                     Negative
November 14, 000                       Negative
September 21, 2000                     Negative
November 14, 2000                      Negative
September 21, 2000                     Negative
November 14, 2000                      Negative
September 21,2000                      Negative
November 14,2000                       Negative

Implicated blood donor
(tested approximately
5 months after donation)

February 28, 2001                       1:256
February 28, 2001                      Negative
February 28, 2001                      Negative

(a) IFA, indirect fluorescent antibody; PCR, polymerase chain
reaction; HGE, human granulocytic ehrlichiosis; Ig, immunoglobulin;
ELFA, enzyme-linked fluorescence assay.

(b) Babesia microti IFA= 1:8=negative.

(c) IgM and IgG immunoblots for HGE.

(d) Two hamsters were each inoculated intraperitoneally on April 3
with 0.75 mL of blood obtained on February 28. Giemsa-stained smears
were made from hamster blood obtained twice weekly, for 8 weeks, by
tail snip. The hamsters did not become demonstrably parasitemic.

Acknowledgments

We thank the laboratory staff of the Division of Parasitic Diseases, Centers for Disease Control and Prevention; Adeleh Ebrahimzadeh from the New York City Public Health Laboratory; and Rich Gallo and staff from the New York State (Westchester County) Department of Health.

References

(1.) Boustani MR, Gelfand JA. Babesiosis. Clin Infect Dis 1996;22:611-5.

(2.) Herwaldt BL, Kjemtrup AM, Conrad PA, Barnes RC, Wilson M, McCarthy MG, et al. Transfusion-transmitted babesiosis in Washington State: first reported case caused by a WA 1-type parasite. J Infect Dis 1997;175:1259-62.

(3.) Herwaldt BL, Persing DH, Precigout EA, Goff WL, Mathiesen DA, Taylor PW, et al. A fatal case of babesiosis in Missouri: identification of another piroplasm that infects humans. Ann Intern Med 1996;124:643-50.

(4.) Quick RE, Herwaldt BL, Thomford JW, Garnett ME, Eberhard ML, Wilson M, et al. Babesiosis in Washington State: a new species of Babesia? Ann Intern Med 1993;119:284-90.

(5.) Persing DH, Herwaldt BL, Glaser C, Lane RS, Thomford JW, Mathiesen D, et al. Infection with a babesia-like organism in northern California. N Engl J Med 1995;332:298-303.

(6.) McQuiston JH, Childs JE, Chamberland ME, Tabor E. Transmission of tick-borne agents by blood transfusion: a review of known and potential risks in the United States. Transfusion 2000;40:274-84.

(7.) Cable RG, Trouern-Trend J. Tickborne infections. In: Linden JV, Bianco C, editors. Blood safety and surveillance. New York: Marcel Dekker; 2001. p. 399-422.

(8.) Filstein MR, Benach JL, White DJ, Brody BA, Goldman WD, Bakal CW, et al. Serosurvey for human babesiosis in New York. J Infect Dis 1980;141:518-21.

(9.) Hatcher JC, Greenberg PD, Antique J, Jimenez-Lucho VE. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis 2001;32:1117-25.

(10.) White DJ, Talarico J, Chang H, Birkhead GS, Heimberger T, Morse DL. Human babesiosis in New York State: review of 139 hospitalized cases and analysis of prognostic factors. Arch Intern Med 1998;158:2149-54.

(11.) Meldrum SC, Birkhead GS, White DJ, Benach JL, Morse DL. Human babesiosis in New York State: an epidemiological description of 136 cases. Clin Infect Dis 1992;15:1019-23.

(12). Chisholm ES, Ruebush TK II, Sulzer AJ, Healy GR. Babesia microti infection in man: evaluation of an indirect immunofluorescent antibody test. Am J Trop Med Hyg 1978;27:14-9.

(13.) Persing DH, Mathiesen D, Marshall WF, Telford SR, Spielman A, Thomford JW. Detection of Babesia microti by polymerase chain reaction. J Clin Microbiol 1992;30:2097-103.

(14.) Wong SJ, Brady GS, Dumler JS. Serological responses to Ehrlichia equi, Ehrlichia chaffeensis, and Borrelia burgdorferi in patients from New York State. J Clin Microbiol 1997;35:2198-205.

(15.) Linden JV, Wong SJ, Chu FK, Schmidt GB, Bianco C. Transfusion-associated transmission of babesiosis in New York State. Transfusion 2000;40:285-9.

(16.) Grabowski EF, Giardina PJV, Goldberg D, Masur H, Read SE, Hirsch RL, et al. Babesiosis transmitted by a transfusion of frozen-thawed blood. Ann Intern Med 1982;96:466-7.

(17.) Slovut DP, Benedetti E, Matas AJ. Babesiosis and hemophagocytic syndrome in an asplenic renal transplant recipient. Transplantation 1996;62:537-9.

(18.) Perdrizet GA, Olson NH, Krause PJ, Banever GT, Spielman A, Cable RG. Babesiosis in a renal transplant recipient acquired through blood transfusion. Transplantation 2000;70:205-8.

(19.) Krause PJ, Lepore T, Sikand VK, Gadbaw J Jr, Burke G, Telford SR III, et al. Atovaquone and azithromycin for the treatment of babesiosis. N Engl J Med 2000;343:1454-8.

Address for correspondence: Brian E. Scully, Department of Medicine, Division of Infectious Diseases, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA; fax: [phone]; e-mail: [e-mail]

Joseph Z. Lux, * Don Weiss, ([dagger]) Jeanne V. Linden, ([double dagger]) Debra Kessler, ([section]) Barbara L. Herwaldt, ([paragraph]) Susan J. Wong, ([double dagger]) Jan Keithly, ([double dagger]) Phyllis Della-Latta, (#) and Brian E. Scully *

* Columbia University College of Physicians and Surgeons, New York, New York, USA; ([dagger]) New York City Department of Health, New York, New York, USA; ([double dagger]) Wadsworth Center, New York State Department of Health, Albany, New York, USA; ([section]) New York Blood Center, New York, New York, USA; ([paragraph]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA; and (#) Columbia Presbyterian Medical Center, New York, New York, USA

Dr. Lux is an infectious diseases fellow at Columbia University College of Physicians and Surgeons.