Recurrence of Human Babesiosis Caused by Reinfection

Healthcare professionals must be aware that babesiosis caused by reinfection might occur.

B abesia microti, the primary cause of human babesiosis, is an intraerythrocytic protozoan that is transmitted by hard-bodied ticks to mammalian hosts and occasionally to humans (1). White-footed mice are the primary host and once infected may remain so for life. Parasitemia also persists in humans, even after antimicrobial drug therapy (2)(3)(4)(5)(6)(7). Immunocompetent human hosts can experience asymptomatic infection for as long as 1 year after antimicrobial drug therapy, although most patients clear infection within several months. Patients who are immunocompromised generally have a longer duration of infection and may experience relapsing symptoms. These patients might remain parasitemic for as long as 2 years, despite antimicrobial drug therapy (5,7). Most patients recover without longterm complications, although babesiosis can result in fatal illness (1,6).
We report a case of babesiosis in a previously healthy patient who experienced a second episode of babesiosis 3 years after an initial episode. He was given a standard course of antimicrobial drugs for Babesia infection for each episode.

The Study
A 62-year-old physician living in Huntington, Long Island, New York, USA, was in good health until June 9, 2013, when he felt unwell and fever, chills, headache, myalgias, fatigue, sweats, joint pain, poor appetite, and conjunctivitis developed. On the third day of illness, he noted dark urine that lasted for several days. On June 13, he was seen by his family physician, who noted fever but no other abnormality.
Subsequent attempts to perform Babesia wholegenome sequencing on a residual blood sample obtained 3 days after the start of treatment identifi ed B. microti DNA, but it was insuffi cient to perform fullgenomic sequencing. At a follow-up visit to his physician on July 5, a CBC and tests for aspartate and alanine aminotransferase levels showed results within references ranges.
Three years later, on June 19, 2016, the patient had fever (temperature 100°F), chills, sweats, headache, myalgias, anorexia, and diffi culty concentrating develop. He also noted dark urine for several days. On June 22, he was seen by his physician, who obtained a CBC, which showed a hemoglobin level of 12.6 g/dL and hematocrit of 38.3%; a leukocyte count of 4,700 cells/µL with 55% neutrophils and 30% lymphocytes; and a platelet count of 41,000 cells/µL. A blood smear showed a Babesia parasitemia level of 1%. We amplifi ed B. microti DNA by using PCR. Results for B. microti antibody were positive (IgM titer 1:256, IgG titer >1;1,024) (Table). He was then given atovaquone (750 mg every 12 h) and azithromycin (500 mg on day 1 and then 250 mg 1×/d) for 10 days, at which time symptoms had resolved. A repeat blood smear did not show any parasites. The patient has subsequently been in good health.

Conclusions
This patient had 2 separate episodes of B. microti babesiosis 3 years apart. He lived in an area where B. microti was hyperendemic and showed typical symptoms of Babesia infection during each episode, including dark urine that is indicative of hemoglobinuria (8). In the fi rst episode, he did not have a blood smear or PCR performed, but a high B. microti IgM response was suggestive of B. microti infection (1,9). B. microti infection was subsequently confi rmed by identifi cation of B. microti DNA. In the second episode, B. microti infection was confi rmed by blood smear and PCR.
Both clinical and laboratory evidence support reinfection rather than relapse of infection for this patient. He was repeatedly exposed to ticks in an area Babesiosis developed in a 62-year-old immunocompetent physician, who had an uneventful recovery after receiving atovaquone and azithromycin. Three years later, babesiosis developed again, and he was again successfully given treatment. Clinical and laboratory evidence were highly supportive of Babesia reinfection. Healthcare professionals should be aware that reinfection might occur in babesiosis.

Recurrence of Babesiosis Caused by Reinfection
where babesiosis is commonly reported (1). He was in good general health without evidence of immunosuppression, whereas all cases of relapsing babesiosis have been reported in immunocompromised persons. After the first episode of babesiosis, he had complete clinical recovery 2 weeks after the onset of infection and did not experience the second episode until 3 years later. In contrast, those persons who have had relapsed B. microti infection have all been immunocompromised, experienced relapses of infection 2 weeks to 3 months after the previous episode, and usually lack full clinical recovery between relapses (3-7). Finally, our patient had a robust B. microti IgM response 2 weeks after the onset of his first infection and an anamnestic antibody response with a high IgG titer on day 4 of the second infection, which is characteristic of reinfection rather than relapse. Patients who have experienced relapse have conditions that impair antibody response (e.g., B cell lymphoma, rituximab therapy, HIV/AIDS). A minimal or absent B. microti antibody response has been demonstrated in patients who have had relapsing babesiosis and have been tested for B. microti antibody (5,7).
Previous studies describe the persistence of human B. microti infection and clinical immunity. In a prospective study of babesiosis patients who were tested for B. microti DNA by PCR every 3 months after acute illness until infection cleared, parasitemia persisted up to 13 months in 22 antimicrobial drugtreated patients and up to 27 months in 23 untreated patients (2). In another study, a patient was reported as having relapsing infection that persisted for 27 months (5). The immediate host response to B. microti infection is provided by innate immune elements that include the spleen, macrophages, and neutrophils. In contrast, long-term clearance of B. microti parasites depends in large part on antibody (2)(3)(4)(5)(6)(7). Studies of the duration of B. microti antibody have demonstrated persistence for as little as 6 months and as long as 6 years (2,6,(10)(11).
Although there is strong evidence that our patient experienced reinfection, we do not have absolute confirmation, and it is possible that he could have had persistent B. microti infection that relapsed after 3 years. No B. microti PCR (or blood smear) was obtained after the initial infection. We attempted to further distinguish between relapse and reinfection by genetic sequencing of B. microti DNA from blood samples obtained from both episodes of infection. Unfortunately, we were unable to obtain sufficient DNA from the first episode for sequencing because a blood sample was only available 3 days after antimicrobial drug therapy was initiated, leaving few viable parasites.
In summary, our study shows evidence of reinfection after successful treatment of a B. microti infection. Although the evidence is highly supportive, it is not definitive. Whether our patient experienced reinfection or relapse 3 years after the initial infection, investigation of similar patients could provide useful information about the immune response to B. microti infection. Patients who have experienced babesiosis, and their healthcare professionals, need to be aware that babesiosis reinfection might occur, as for Lyme disease (12,13). Tickborne disease preventive measures should be maintained for patients with or without a history of babesiosis (14).
This study was supported in part by the Gordon and Llura Gund Foundation.

About the Author
Dr. Ho is a resident of internal medicine at Rhode Island Hospital/Warren Alpert Medical School, Brown University, Providence, RI. His research interests include antimicrobial drug resistance and quality care in gastroenterology.