Thrombocytopenia in a Febrile Neonate

A 30-day-old healthy female with no medical history presents in February with 1 day of fever of 100.9 °F (38.3 °C) and 3 days of congestion and rhinorrhea. The parents deny their daughter has emesis, diarrhea, or behavior change. She continues to feed well and has normal urine and stool output. She was born at 40 weeks gestation to a G1P1 mother. Prenatal labs were unremarkable, including negative group B Streptococcus (GBS), HIV, syphilis, gonorrhea, chlamydia, hepatitis B and C testing, and immunity to rubella and varicella. Pregnancy, delivery, and postnatal course were uncomplicated. The patient received her hepatitis B vaccine at delivery. Her birthweight was in the 75th percentile, and she is growing along her growth curves. She is formula- and breastfed, and her mother takes no medications. She is not in daycare, there are no known sick contacts, and there is no history of travel. The family has a pet dog. She lives in a wooded area of southern New Jersey and spends limited time outdoors.In the emergency department, her temperature is 102.2 °F (39 °C), heart rate is 185 beats/min, respiratory rate is 58 respirations/min, and blood pressure is 94/45 mm Hg. On physical examination, conjunctivae are clear, and no lymphadenopathy is appreciated. Her lungs are clear to auscultation without focal findings. Her cardiovascular exam reveals a regular rhythm, no murmur, euvolemia, and a normal capillary refill. Her abdominal exam is soft and nontender; her liver is enlarged, with liver edge 2 cm palpated below the costal margin with no splenomegaly. She has no rashes. The initial laboratory assessment is significant for thrombocytopenia (32 × 109/L), elevated inflammatory markers (C-reactive protein 6.6 mg/dL; procalcitonin 1.07 ng/mL), normal hemoglobin level (10.9 g/dL, reference range 10.0–18.0 g/dL) and slightly elevated white blood cell (WBC) count (15.4 × 109/L, reference range 8.4–14.4 x109/L), with 31% neutrophils and 57% lymphocytes. Liver enzymes are within normal limits (alkaline phosphatase 146 U/L, alanine aminotransferase 43 U/L, and aspartate aminotransferase 127 U/L on a hemolyzed sample). Bilirubin is slightly elevated to 1.8 mg/dL. Coagulation studies are normal (prothrombin time 15.3 seconds, partial thromboplastin time 30.2 seconds). Urinalysis shows negative leukocyte esterase, nitrites, and bilirubin. A lumbar puncture reveals reassuring cerebrospinal fluid (CSF) indices (2 WBC/μL, 5 red blood cell [RBC]/μL, glucose 54 mg/dL, total protein 35mg/dL). Respiratory viral panel is negative for COVID-19, respiratory syncytial virus, and influenza. She is admitted and treated with empirical antibiotics of ampicillin and ceftriaxone.Blood, urine, and CSF cultures demonstrate no growth at 24 hours. A repeat complete blood count (CBC) finds stable platelets (35 × 109/L) with a decrease in hemoglobin (8.0 g/dL) and elevated reticulocytes of 4.2%. A peripheral blood smear is performed. Herpes simplex virus (HSV) and additional viral testing is deferred given early identification of an alternate diagnosis.The differential diagnosis for this febrile infant with thrombocytopenia included:Viral infection: Viral infections are thought to account for over half of admissions of febrile neonates in the United States.1 Even when viral studies are sent, numerous common viruses are unidentified by typical testing paradigms. Viral infection commonly causes fever and upper respiratory symptoms and can cause thrombocytopenia and anemia through bone marrow suppression. Viral etiologies that cause fever and thrombocytopenia include cytomegalovirus, HIV, HSV, and enteroviruses.2 Fungal etiologies were considered2 but less likely in an immunocompetent, healthy, term neonate.Bacterial infections: Thrombocytopenia in a febrile infant is concerning for invasive bacterial infection.3 Bacterial pathogens of concern in this age group include GBS, Staphylococcus aureus, enteric gram negatives (most commonly Escherichia coli), and Listeria monocytogenes. Blood, CSF, and urine studies were collected to evaluate these etiologies. Congenital syphilis was in the differential but less likely given the negative maternal serologies. There was no evidence of skin, soft tissue, gastrointestinal, musculoskeletal, or pulmonary focus on physical exam to suggest alternate source of bacterial infection. Disseminated intravascular coagulation (DIC) due to infection was considered as a source of thrombocytopenia, but there were no signs of coagulopathy.Vector-borne/zoonotic infections: Vector-borne or zoonotic illnesses were considered less likely due to limited exposure history as well as the winter season in the Mid-Atlantic region. With anemia and thrombocytopenia, the differential includes malaria, dengue fever, babesiosis, and toxoplasmosis, depending on an infant’s prior exposures and place of birth as well as seasonality of pathogens.Neonatal alloimmune thrombocytopenia (NAIT): NAIT is the most common cause of severe thrombocytopenia in the neonatal period.4 Presenting symptoms include bleeding, petechiae, and purpura, with platelet counts generally below 50 000/μL (50 × 109/L).5 Because the pathogenesis of thrombocytopenia is maternal antibodies to fetal platelet alloantigens,6 symptoms and platelet counts typically resolve by 2 weeks of life.5 Fever has not been consistently associated with this condition. Malignancy was considered but less likely given the patient’s age, excellent growth, and acute presentation.The peripheral blood smear revealed intraerythrocytic parasites (Figure 1), consistent with malaria or babesiosis. Thick and thin smear confirmed intracellular parasites with parasite level (percent of infected RBCs) of 8.9% and morphology consistent with Babesia. The diagnosis was subsequently confirmed by polymerase chain reaction (PCR).Further history revealed no travel history to malaria-endemic areas for the mother or the patient. The family lived in a wooded area of southern New Jersey, but the infant had no known tick bites. Mom had a remote history of tick bites prior to pregnancy. She did not have any unexplained fevers, thrombocytopenia, or anemia during pregnancy. The mother did not undergo serologic testing for babesiosis given low clinical utility because this assay does not reliably distinguish acute disease from prior infection. She was asymptomatic, and therefore, treatment would not be indicated. Based on the lack of exposure history in the neonate, birth during winter with low prevalence of ticks in the region, and literature review, a presumed diagnosis of vertically transmitted babesiosis was made.Babesiosis is classically a tickborne illness caused by the protozoan Babesia microti and is spread by the tick genus Ixodes.7 Symptoms typically arise 1 to 4 weeks after tick bite. Fever and fatigue are the most common symptoms of Babesia infection; hemolytic anemia, thrombocytopenia, and hepatosplenomegaly are also common.8,9 Anemia and thrombocytopenia are secondary to innate immune response to infection and cell lysis, while hepatosplenomegaly is secondary to sequestration of infected cells.9 While most pediatric cases have mild symptoms, severe manifestations in older adults or immunocompromised individuals include acute respiratory distress syndrome (ARDS), DIC, and prolonged relapsing course despite antibiotic therapy.9 The endemic region for B. microti lies in the Northeastern and Northern-Midwestern regions of the Unites States during warm spring and summer months and has rapidly expanded southward to Florida and westward to South Dakota over the last decade.10PCR is the diagnostic gold standard, but peripheral blood smear can reveal intracellular inclusions that form a “Maltese cross,” the hallmark pathologic finding of babesiosis (Figure 1). As in this case, this finding often precedes PCR results and is a helpful diagnostic tool. Serial parasite levels are helpful to evaluate effectiveness of antimicrobials and correlate with clinical status.Vertical transmission of Babesia infection has been appreciated as an additional route of infection in mammals.7,11,12 This case represents the 13th reported case of congenital babesiosis in the literature13–23 (Table 1). The most common presenting findings are fever (12/13, 92% of cases) and thrombocytopenia (12/13, 92%), with fewer patients presenting with anemia (6/13, 46%). Severity of anemia and thrombocytopenia did not correlate with parasite load when analyzed across all cases. Severe sequelae of babesiosis were not observed in congenital cases, with no documented cases of ARDS, DIC, or splenic rupture.Vertical transmission occurs via transplacental spread from mother to fetus. While this case had no confirmed maternal infection, asymptomatic parasitemia occurs in endemic areas.24 One study found B. microti antibodies in 1% of all healthy, asymptomatic blood donors, with more than half of seropositive donors having active parasitemia.24 Notably, the age of presentation of symptomatic infants with congenital babesiosis is between 19 and 42 days of life, regardless of timing of maternal infection, while congenital malaria typically presents earlier at 10 to 30 days of life.25 This may reflect differences in mechanism of neonatal infection or virulence of these parasites; further investigation is necessary to elucidate this phenomenon.While babesiosis can be a self-limited illness in children and adults, the illness course appears more severe in infants. More than 80% of documented cases of vertically transmitted babesiosis have required packed RBC transfusion to treat severe anemia (Table 1). Antimicrobial treatment regimens for symptomatic Babesia infection have evolved. While early reports utilized clindamycin and quinine,13,14,18 consensus guidelines now recommend atovaquone and azithromycin because this regimen has a more favorable side-effect profile and remains effective.26 While the use of azithromycin in infants younger than 6 weeks old has been associated with infantile hypertrophic pyloric stenosis, the risks and benefits were weighed in this case and deemed acceptable for use.Treatment with azithromycin and atovaquone was initiated. Her anemia worsened with lowest recorded hemoglobin of 6.7 g/dL. She required two 10 mL/kg (1 × 10−2 L/kg) packed RBC transfusions. Her platelet levels remained stable without platelet transfusions. On day 7 of treatment, laboratory studies demonstrated stabilizing hemoglobin, normal platelet level, and undetectable parasite levels on peripheral blood smear, and she was discharged home. She completed a total 14-day antimicrobial course, with undetectable parasite levels and reassuring CBC parameters at 4-week follow-up.Thrombocytopenia in febrile neonate should prompt a broad differential diagnosis beyond typical bacterial and viral pathogens; a peripheral blood smear can be an important diagnostic test in these cases.History of maternal tick exposure should prompt consideration of testing for Babesia infection in an infant with fever and thrombocytopenia.Management of neonatal babesiosis includes antibiotics and supportive care, including blood component transfusions as clinically indicated.We would like to acknowledge Dr Benjamin Philipson for his contributions to this report. We would also like to thank Drs Andrew Handel and Shweta Iyer for providing additional details about their previously reported cases.