Relationship Between Neonatal Leukemoid Reaction and Bronchopulmonary Dysplasia in Low-Birth-Weight Infants: A Cross-Sectional Study

ABSTRACT

Leukemoid reaction in low-birth-weight (LBW) infants is a rare, recently documented phenomenon, implicated in the sequence of multiorgan inflammatory diseases of preterm infants. The aim of the present paper is to establish whether a neonatal leukemoid reaction is related to bronchopulmonary dysplasia (BPD) development in LBW infants. The design was a case-controlled, retrospective study of all premature infants (born ≤31 weeks' gestation) admitted to the neonatal intensive care unit (NICU) over a period of 3 years, from January 1998 to December 2000. The infants who developed BPD formed the study group, while the remainder without pulmonary sequelae, matched for gestational age formed the control group. Leukemoid reaction was considered a white blood cell (WBC) count >40,000/mm³. The relation between BPD occurrence and WBC counts was studied by Bayesian analysis, dividing WBC counts in 5 progressive bands of 10,000 WBC/mm³, starting from <10,000 to >40,000/mm ³ . Five of 50 BPD infants studied demonstrated WBC counts >40,000/mm³, with an incidence of 10%, while no control preterm infants presented neonatal leukemoid reaction; the estimated number difference is statistically significant (p <0.001). There was no other significant association demonstrated between maternal or neonatal variables and leukemoid reaction, including chorioamnionitis, sepsis, and the use of antenatal steroids. Our findings provide further data for the identification of prematures exposed to pro-inflammatory cytokines in utero; the injury responsible for BPD in a subset of prematures may begin with a transient leukemoid reaction.

KEYWORDS

Bronchopulmonary dysplasia - granulocyte-colony stimulating factor - leukemoid reaction - low-birth-weight infants

REFERENCES

• 1 Bancalari E. Changes in the pathogenesis and prevention of chronic lung disease of prematurity.  Am J Perinatol . 2001;  18 1-8
• 2 Gomez R, Ghezzi F, Romero R, Munoz H, Tolosa J E, Rojas I. Premature labor and intra-amniotic infection: clinical aspects and role of the cytokines in diagnosis and pathophysiology.  Clin Perinatol . 1995;  22 281-342
• 3 Yoon B H, Romero R, Jun J K. Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 and the risk for the development of bronchopulmonary dysplasia.  Am J Obstet Gynecol . 1997;  177 825-830
• 4 Hallman M. Cytokines, pulmonary surfactant and consequences of intrauterine infection.  Biol Neonate . 1999;  76 2-9
• 5 Kohelet D, Arbel E, Ballin A, Goldberg M. Variations in neutrophil count in preterm infants with respiratory distress syndrome who subsequently develop chronic lung disease.  Am J Perinatol . 2000;  3 159-162
• 6 Groneck P, Gotze-Speer B, Oppermann M, Eiffert H, Speer C P. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates.  Pediatrics . 1994;  93 712-718
• 7 Watterberg K L, Demers L M, Scott S M, Murrphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.  Pediatrics . 1996;  97 210-215
• 8 Gillan E R, Christiansen R D, Suen Y, Ellis R, van de Ven C, Cairo M S. A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia.  Blood . 1994;  84 1427-1433
• 9 Cairo M. Therapeutic implications of disregulated colony-stimulating factor expression in neonates.  Blood . 1993;  82 2269-2272
• 10 Calhoun D A, Kirk J, Christensen R D. Incidence, significance, and kinetic mechanism responsible for leukemoid reactions in patients in the neonatal intensive care unit: a prospective evaluation.  J Pediatr . 1996;  129 404-409
• 11 Cannistra S A, Griffin J. Regulation of the production and function of granulocytes and monocytes.  Semin Hematol . 1988;  25 173-188
• 12 Nathan D G. Regulation of hematopoiesis.  Pediatr Res . 1990;  27 423-431
• 13 Ernst T J, Ritchie A R, Demetri G D, Griffin J D. Regulation of granulocyte- and monocyte-colony stimulating factor mRNA levels in human blood monocytes is mediated primarily at a post-transcriptional level.  J Biol Chem . 1989;  264 5700-5703
• 14 Vellenga E, Dokter W, deWolf J TM, van de Vinne B, Esselink M T, Halie M R. Interleukin-4 prevents the induction of G-CSF mRNA in human adherent monocytes in response to endotoxin and IL-1 stimulation.  Br J Haematol . 1991;  79 22-26
• 15 Bancalari E, Abdenour G E, Feller R, Gannon J. Bronchopulmonary dysplasia: clinical presentation.  J Pediatr . 1979;  95 819-823
• 16 Ballard J L, Novak K K, Driver M. A simplified score for assessment of newly born infant.  J Pediatr . 1979;  95 732-735
• 17 Moore T R, Cayle J E. The amniotic fluid index in normal human pregnancy.  Am J Obstet Gynecol . 1990;  162 1168-1173
• 18 Naeye R L, Maisels J, Lorenz R P, Botti J J. The clinical significance of placental villous edema.  Pediatrics . 1983;  71 588-594
• 19 Gurrin L C, Kurinczuk J J, Burton P R. Bayesian statistics in medical research: an intuitive alternative to conventional data analysis.  J Eval Clin Pract . 2000;  6 193-204
• 20 Rastogi S, Rastogi D, Sundaram R, Kulpa J, Parekh A J. Leukemoid reaction in extremely low-birth-weight infants.  Am J Perinatol . 1999;  16 93-97
• 21 Gessler P, Kirchmann N, Kienntch-Engel R, Hass N, Lasch P, Kachel W. Serum concentration of granulocyte stimulating factor in healthy term and preterm neonate and in those with various diseases including bacterial infection.  Blood . 1993;  32 3177-3188
• 22 Brus F, van Oeveren W, Okken A, Oetomo S B. Activation of circulating polymorphonuclear leukocytes in preterm infants with severe idiopathic respiratory distress syndrome.  Pediatr Res . 1996;  39 456-463
• 23 Gomez R, Romero R, Ghezzi F, Yoon B, Mazor M, Berry S M. The fetal inflammatory response syndrome.  Am J Obstet Gynecol . 1998;  179 194-202
• 24 Merritt T A, Cochrane C G, Holcomb K. Elastase and alpha 1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome: role of inflammation in the pathogenesis of bronchopulmonary dysplasia.  J. Clin Invest . 1983;  72 656-666
• 25 Bry K, Hallman M, Teramo K, Waffarm F, Lappalainen U. Granulocyte-macrophage colony-stimulating factor in amniotic fluid and in airway specimens of newborn infant.  Pediatr Res . 1997;  41 105-109
• 26 Calhoun D A, Rosa C, Christensen R D. Transplacental passage of recombinant human granulocyte colony-stimulating factor in women with an imminent preterm delivery.  Am J Obstet Gynecol . 1996;  174 1306-1311
• 27 Speer C, Groneck B. Oxygen radicals, cytokines, adhesion molecules and lung injury in neonates.  Semin Neonatal . 1998;  3 212-228