https://orcid.org/0000-0003-3544-4376
CASE REPORT
A male infant of 33 weeks’ gestation, with appropriate weight for age, was born in August on Long Island, New York, to a previously healthy 24-year-old woman. Six weeks earlier, the mother had experienced flu-like symptoms and multiple “bull’s-eye” lesions. A Borrelia burgdorferi immunoglobulin G (IgG)/immunoglobulin M (IgM) enzyme immunoassay (EIA) was positive at that time, but a reflex Western blot was not performed. Babesia testing was also not obtained. Her symptoms improved with a 2-week course of amoxicillin, though she continued to experience numbness of the right hip and shoulder. Following delivery, she received a 3-week course of cefuroxime, again without improvement. The numbness eventually resolved following 4 weeks of intravenous ceftriaxone.
The infant was delivered via emergent cesarean section due to an unexpected placental abruption. Shortly after birth, the infant was admitted to the neonatal intensive care unit (NICU) due to prematurity and moderate respiratory distress. The mother’s peripartum complete blood count (CBC) then revealed anemia, thrombocytopenia, and 1% intra-erythrocytic parasitemia. A presumptive diagnosis of babesiosis was made based on the recent history of Lyme disease and lack of travel exposure to malaria. Gross and microscopic placenta evaluation was negative for microbes or signs of infection. The mother was treated with 10 days of atovaquone and azithromycin, with subsequent parasitemia resolution.
On day of life 1, the infant’s Babesia blood smear and polymerase chain reaction (PCR) assay were negative. He remained admitted to the NICU for 3 weeks. Blood smears and Babesia PCR, all obtained via venipuncture, were repeated weekly until discharge, with a typical hemoglobin trend throughout admission (Figure 1).
Timeline of clinical events showing laboratory results and antibiotics prescribed from birth through resolution of babesiosis relapse. Abbreviations: Hb, hemoglobin; neg, negative; PCR, Babesia polymerase chain reaction; pos, positive.
A repeat Babesia PCR obtained at discharge (3 weeks old) returned positive, prompting outpatient treatment with a 10-day course of oral azithromycin (15 mg/kg once daily; high dose selected due to limited neonatal dosing data and relatively immunocompromised state) and atovaquone (20 mg/kg/dose every 12 hours, taken with breast milk to improve absorption). On treatment day 4, rare intra-erythrocytic parasites were identified on thick, but not thin, blood smear. Species-specific PCR testing (Wadsworth Center, New York State) confirmed the presence of Babesia microti. The infant was also neutropenic for age throughout the illness. Multiple blood smears obtained upon treatment completion, at 5, 6, and 7 weeks old, were negative for parasites.
At 8 weeks old, the infant developed a quarter-sized erythematous patch on the right lower abdomen. The lesion expanded outward with central clearing, raising concern for a single erythema migrans. Evaluation for Lyme disease was undertaken. Lyme disease serology showed a reactive B. burgdorferi whole-cell sonicate EIA, and a reflex Western blot revealed no IgM bands and 2 IgG bands; B. burgdorferi C6 peptide antibody EIA was also positive (7.98, positive >1.09). His mother’s testing, obtained simultaneously, similarly showed a reactive whole-cell sonicate EIA, a Western blot with 1 IgM band and the same 2 IgG bands, and a positive C6 peptide antibody EIA (8.33). The infant’s blood was negative for B. burgdorferi by PCR. A punch biopsy obtained from the leading edge of the skin lesion was also negative by PCR for B. burgdorferi. Though his testing indicated absence of B. burgdorferi infection, the infant was treated with 14 days of amoxicillin.
Laboratory testing was repeated periodically to monitor for Babesia recurrence. At 12 weeks old, his hemoglobin decreased to 6.3 g/dL, blood smear again showed parasitemia (0.3%), and he seemed to sleep more than usual. He was briefly admitted to the general pediatric unit where he received 1 packed red blood cell transfusion, and a 6-week course of oral azithromycin (10 mg/kg on day 1, then 5 mg/kg once daily) and atovaquone (20 mg/kg/dose every 12 hours) was started.
During the following 3 weeks, his activity level improved, though low-grade parasitemia (0.1%–0.3%) persisted. This prompted the addition of a 3-week course of clindamycin (10 mg/kg/dose 3 times daily) at 15 weeks old. Repeat blood smear 5 days later was negative for parasites, as were all subsequent smears. He completed a total 6-week course of antibiotics during the relapse. Two weeks after completing the antibiotics (at age 20 weeks), a repeat blood smear was negative and his hemoglobin was at its highest point in 8 weeks. Four weeks later (age 24 weeks), a Babesia blood PCR was negative.
A targeted immune evaluation was undertaken to explain his babesiosis relapse. Maternal human immunodeficiency virus (HIV) screening was negative. The infant’s neutropenia resolved, and lymphocyte flow cytometry and quantitative immunoglobulins were normal. Hyposplenism was unlikely, as an ultrasound showed a normal spleen size and appearance, and there were no red blood cell Howell-Jolly bodies. Six months after completing treatment for the relapsed babesiosis, there is no evidence of a second relapse.
Discussion
Our report describes the first documented case of relapsed babesiosis in a vertically infected neonate. This case is notable for a number of unusual occurrences, including the mother’s preterm labor presumably caused by untreated babesiosis, the infant’s babesiosis diagnosis by PCR prior to symptoms, and the need to treat with 2 antibiotic courses.
Infants with transplacental babesiosis typically become ill between 3 and 6 weeks of age [1]. The presenting findings are nonspecific and include fever, irritability, poor feeding, pallor, and hepatosplenomegaly. Considering the rarity of the infection among neonates and the lack of specific clinical features, babesiosis is not typically suspected in this population. Most commonly, the CBC manual differential reveals intra-erythrocytic parasites, limiting the causative agent to Babesia species based on the patient’s geographic location. Diagnosis may be confirmed with whole blood Babesia PCR and maternal laboratory evaluations including convalescent antibody titers, PCR, or direct Babesia visualization. Once the infection is identified, infants are most often treated with a combination of atovaquone and azithromycin.
Though pregnant women are at increased risk of developing symptomatic babesiosis and symptoms mimicking Hemolysis, Elevated Liver enzymes, Low Platelet count syndrome, subsequent preterm labor is rare [2]. In our patient’s case, we presume that the placental abruption, in the setting of parasitemia, anemia, and thrombocytopenia, was due to babesiosis. As the mother had been diagnosed with Lyme disease 6 weeks earlier, this case suggests potential benefit to screening pregnant women infected with Lyme disease and living in a Babesia-endemic region. Due to the lack of published cases, however, optimal management of gestational babesiosis remains unknown.
Infants born to mothers with babesiosis at the time of delivery should be followed closely for transplacental infection. We repeated the infant’s Babesia PCR assays weekly, leading to his presymptomatic diagnosis. We also monitored serial hemoglobin levels, as a rapid decrease would suggest babesiosis. Our patient had an increased reticulocyte count and laboratory evidence of hemolysis, consistent with red blood cell destruction rather than anemia of prematurity and the physiologic nadir.
Optimal timing for treatment of vertically acquired babesiosis is unknown. There are no data to support or discourage presumptive treatment of the infant upon delivery. In our case, the potential adverse medication effects, particularly pyloric stenosis due to azithromycin, outweighed the potential benefits. As we are unaware of other reports of relapsed transplacental babesiosis, ideal antibiotic therapy is also unknown. Based on adult data [3], we selected a repeat course of azithromycin and atovaquone for a duration of 6 weeks, including a 3-week course of clindamycin when parasitemia persisted. It is unclear if the clindamycin eradicated the parasites or was a coincidence in timing.
The lack of data regarding risk factors for transplacental babesiosis relapse led us to rely on data from older patients. Adults with relapsed or severe disease often have preexisting asplenia, hematologic malignancy, HIV, or use of rituximab or other immunosuppressive medications [3]. Our infant lacked evidence of asplenia or hyposplenism, had no evidence of malignancy, and no exposure to rituximab or other immunosuppressants. Aside from Babesia-induced neutropenia that resolved with antibiotics, his primary immunodeficiency laboratory screening was normal. Antibiotic-resistant babesiosis was also considered but deemed unlikely, as this usually leads to a sharp rise in parasitemia [4]. This narrowed the differential diagnosis to inadequate dosing or medication administration, poor oral absorption, and prematurity. In addition, the infant likely received minimal anti-Babesia antibodies from his mother due to his prematurity and her infection only weeks before delivery. In this case, multiple predisposing factors likely contributed to the relapse.
Finally, the infant had an erythema migrans–like rash, raising concern for concomitant Lyme disease. The data supporting vertical transmission of B. burgdorferi are scant at best, with such infections occurring extremely rarely, if at all [5]. Our patient had a lower C6 peptide antibody than his mother, no IgM antibodies, and a negative skin biopsy PCR, making Lyme disease extremely unlikely. Nonetheless, a 14-day course of amoxicillin was administered to eliminate any future concerns regarding an untreated neonatal B. burgdorferi infection.
In summary, our report describes the first known occurrence of relapsed babesiosis in a vertically infected neonate. This case suggests a potential benefit to testing pregnant women who live in a Babesia-endemic region and are infected with Lyme disease for concurrent babesiosis. We suggest obtaining serial Babesia PCR and hemoglobin levels from neonates born to mothers with babesiosis at delivery. Our patient’s relapse was adequately treated with a prolonged course of atovaquone, azithromycin, and clindamycin.
Notes
Acknowledgments. We wish to acknowledge the infant and his family for allowing us to publish this report.
Potential conflicts of interest. Authors: No reported conflicts of interest.
Authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
