Leukemoid Reaction: Rare Presentation of Extremely Preterm Neonates

Case Report

A primigravida mother on a regular antenatal followup presented 48 hours prior to delivery with pain in lower abdomen and was diagnosed to have urinary tract infection. She was started on oral antibiotics and tocolytics and discharged. As mother had suspected preterm labor pains and the risk of imminent preterm delivery, two doses of antenatal steroids (Betamethasone) were administered 24 h apart. The mother presented in labor after 48 h with ruptured membranes and compound presentation (head with hand).

An extremely preterm (25 weeks, 4 days), extremely low birth weight (670 g) female baby was born vaginally, who was given continuous positive airway pressure (CPAP) at the birth delivery room followed by nasal bubble CPAP. The anatomical examination of placenta and umbilical cord reveals normal functioning. Both umbilical venous and arterial catheterization were performed and the baby was started on total parenteral nutrition and minimal enteral nutrition within 12 h of life. Owing to extremely premature birth, prolonged rupture of the membrane, and respiratory distress, the intravenous antibiotics piperacillin/tazobactam and amikacin were started as per the unit policy and pending blood culture report. The baby had clinically no dysmorphism suggestive of trisomy 21. The baby had apnea on day 1. She was given intravenous caffeine citrate and continued on caffeine maintenance.

The initial white blood cell (WBC) count on day 1 was 43 × 10⁹ per liter (differential count (DLC): 80% neutrophils, 10% lymphocytes, 4% metamyelocytes, 2% myelocytes, and 34,480/cumm absolute neutrophil count [ANC]). At 24 h of life, the baby was diagnosed to have patent ductus arteriosus clinically and echocardiographically and was treated with oral paracetamol. Investigations were repeated 48 h later with an increase in WBC to 117.7 × 10⁹ per liter (DLC: 62% neutrophils, 10% lymphocytes, 12% metamyelocytes, 10% myelocytes, and 72,975/cumm ANC). No anemia or thrombocytopenia was observed. The review ECHO was normal. Cranial USG done at 72 h of life reveals normal functioning. Antibiotics were stopped after 72 h as C-reactive protein remained within normal limits, blood culture remained sterile, and the clinical course was inconsistent with sepsis. The complete blood count repeated at 96 h of life showed a decreasing trend. The baby showed no complications associated with hyperleukocytosis (Figure 1).

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Figure 1.

Hyperleukocytosis on Peripheral Blood Film with Immature Forms Suggestive of Leukemoid Reaction

Discussion

The total WBC count and neutrophil count in neonates younger than 1 week are physiologically higher than those of children and adults and the counts usually range from 9000 to 30,000/cumm. ¹ This physiological leukocytosis is mediated by several molecules, which are released or upregulated in response to stimulatory events that include growth or survival factors (eg, granulocyte colony-stimulating factors (G-CSF), granulocyte-macrophage colony-stimulating factors (GM-CSF), and c-kit ligand), adhesion molecules, and various cytokines (eg, IL-1,3,6,8,tumornecrosisfactor). ² Hyperleukocytosis is commonly observed but extreme hyperleukocytosis is a rarely diagnosed condition. In this case report, we mention that a newborn extremely preterm at 25 weeks born by vaginal delivery develops hyperleukocytosis (>100 × 10⁹ per liter) with leukemoid reaction (LR). Congenital leukemia presents clinically with hepatosplenomegaly, lymphadenopathy, and skin manifestations. Hyperleukocytosis is present in 85% of acute lymphoid leukemia patients and 49% of acute myeloid leukemia patients.^{3, 4} Anemia and thrombocytopenia are associated with neonatal leukemia. Transient myeloproliferative disorder (TMD) of Down’s syndrome is generally associated with thrombocytopenia. ⁵ Similarly, the leukocyte adhesion defect presents commonly with delay in umbilical cord sloughing generally within 7 to 10 days of life. Since the baby had no signs or symptoms of congenital leukemia, TMD of Down’s syndrome, no thrombocytopenia, and no skin manifestation, there was a possibility of LR being attributable to extreme prematurity and antenatal steroids (ANS).

ANS are known to increase the leukocyte count by accelerating the release of neutrophils from bone marrow and decreasing egress from the circulation. Hsai and Omar, ⁶ in their study, showed that the LR and no-LR groups had similar exposure to ANS and exhibited a similar pattern of ANC changes, with the peak values occurring around the second week of life, which is beyond the theoretical range of the ANS effect as observed in the previous clinical studies.^{7, 8} Therefore, the contribution of ANS to the occurrence of LR is limited. The leukemoid reaction in extremely low birth weight infants is associated with a prolonged need for ventilatory support and oxygen requirement, higher incidence of bronchopulmonary dysplasia (BPD), and a tendency for lower mortality. The leukemoid reaction may be a manifestation of the immature inflammatory cascade activated in response to perinatal or neonatal insult and stress. A growing body of evidence suggests that early activation and transendothelial migration of neutrophils have been found to be an important contributing factor in the pathogenesis of severe respiratory distress syndrome and its progression to BPD in premature infants. ⁹

Conclusion

In conclusion, extreme hyperleukocytosis with LR is a rarely described condition. In this report, we describe an extremely premature newborn with extreme hyperleukocytosis and LR. Based on the clinical features, investigations, and peripheral blood film, LR was confirmed and the baby was managed with supportive care. No obvious short-term complications of hyperleukocytosis were observed.