sign in sign up
<<
Home , Eosinophil, Monocyte

Journal of Perinatology (2010) 30, 540–545 r 2010 Nature America, Inc. All rights reserved. 0743-8346/10 www.nature.com/jp ORIGINAL ARTICLE Reference ranges for concentrations of and during the neonatal period defined from over 63 000 records in a multihospital health-care system

RD Christensen1,2, J Jensen1,3, A Maheshwari4 and E Henry1,3 1Intermountain Healthcare Women and Newborns Clinical Program, Ogden, UT, USA; 2McKay-Dee Hospital Center, Ogden, UT, USA; 3Institute for Healthcare Delivery Research, Salt Lake City, UT, USA and 4Divisions of Neonatology and Pediatric Gastroenterology, Departments of Pediatrics, Biology, and Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

Introduction Objective: Blood concentrations of eosinophils and monocytes are part Normal values for hematological parameters are not generally of the . Reference ranges for these concentrations during available for neonates because blood is not drawn on healthy the neonatal period, established by very large sample sizes and modern neonates to establish normal ranges. Instead, ‘reference ranges’ are methods, are needed for identifying abnormally low or high values. used in neonatal hematology.1–6 These consist of the 5th to 95th Study Design: We constructed reference ranges for eosinophils per ml percentile values assembled from large numbers of neonates with and monocytes per ml among neonates of 22 to 42 weeks of gestation, minimal pathology or with pathology not thought to be relevant to on the day of birth, and also during 28 days after birth. Data were the laboratory parameter under study. Recent examples of their obtained from archived electronic records over an eight and one-half-year usefulness include the following: Reference ranges for erythrocyte period in a multihospital health-care system. In keeping with the indices3 have enabled identifying neonates with hereditary reference range concept, values were excluded from neonates with a spherocytosis on the basis of an elevated mean corpuscular diagnosis of or necrotizing enterocolitis (NEC). hemoglobin concentration.7 Reference ranges for Result: Eosinophils and monocytes per ml of blood were electronically concentrations4 have enabled a definition of neonatal retrieved from 96 162 records, of which 63 371 that lacked a diagnosis of thrombocytosis,5 and defining altitude-appropriate reference ranges infection or NEC were included in this reference range report. The mean for blood concentrations6 has enabled more precise value for eosinophils per ml on the day of birth increased linearly between 22 identification of neonates with .8 and 42 weeks of gestation, as did the 5 and 95% values. The reference range Abnormal blood concentrations of eosinophils or monocytes at 40 weeks was 140 to 1300 ml–1 (mean 550 ml–1). Similarly, the mean can assist in identifying adults with various pathological value for monocytes increased linearly over this interval, with a reference conditions.9,10 Reference ranges from very large data sets are rangeat40weeksof300to3300ml–1 (mean 1400 ml–1). Over the first 4 lacking for blood concentrations of eosinophils and monocytes weeks after birth, no appreciable change was observed in 5% limit and mean during the neonatal period, particularly among the extremely count, with a slight increase in the 95% limit in week 4. A slight low birth weight neonates who now populate most of the level III increase in count was observed during the first 2 weeks after birth. neonatal intensive care units. Therefore, we constructed reference Conclusion: The results of this analysis describe reference ranges ranges for eosinophils and monocytes of neonates from 22 to 42 for blood concentrations of eosinophils and monocytes during the weeks of gestation on the day of birth, and over the first 28 days neonatal period. Additional study is needed for determining the relevance after birth, using the databases of an 18-hospital system in the of values falling outside the reference range. western United States. Journal of Perinatology (2010) 30, 540–545; doi:10.1038/jp.2009.196; published online 7 January 2010 Methods Keywords: reference range; neonate; eosinophil; monocyte; CBC Information was collected as a de-identified limited data set from archived Intermountain Healthcare records. The information Correspondence: Dr RD Christensen, Department of Neonatology, Intermountain Healthcare, collected was limited to that shown in the figures of this report. 4403 Harrison Boulevard, Ogden, UT 84403, USA. Blood concentrations of eosinophils and monocytes were abstracted E-mail: [email protected] Received 20 August 2009; revised 6 October 2009; accepted 10 November 2009; published online electronically from complete blood counts (CBCs) obtained on 7 January 2010 neonates with a date of birth from 1 January 2002 through 31 May Reference ranges for eosinophils and monocytes RD Christensen et al 541

2009. Values were excluded if a diagnosis was identified anywhere NEC was listed in one or more data-marts, and therefore in the electronic record of infection (bacterial, viral, fungal or these samples were not included in the reference range. protozoal) or necrotizing enterocolitis (NEC). The data fields used Thus, the number of CBC on which the reference range was to identify infection or NEC were International Classification of constructed was 63 371. The exact number of patients at Disease-Ninth Revision, Case Mix (the billing, coding and financial each gestational age contributing data to the reference range is data mart used by Intermountain Healthcare) and EVOX (the shown in Figure 1. extended Vermont-Oxford database). Blood samples were run on a The mean values for eosinophils increased approximately Beckman Coulter LH750 (Fullerton, CA, USA), which is the linearly between 22 and 42 weeks of gestation, as did the 5 and instrument present in all Intermountain Healthcare Hospitals that 95% values. The reference range for eosinophils at 40 weeks of have a level III neonatal intensive care unit.11 Gestational age was gestation was 140 to 1300 ml–1 (mean 550 ml–1; Figure 2). determined by obstetrical assignment unless this was changed by Similarly, the mean values for monocytes increased approximately the neonatal examination. linearly over this interval with a reference range at 40 weeks of 300 The program used for data collection was a modified subsystem to 3300 ml–1 (mean 1400 ml–1; Figure 3). of ‘clinical workstation’. Clinical workstation is a web-based Over the first 4 weeks after birth, no appreciable change was electronic medical record application that stores demographic and observed in 5% limit and mean eosinophil count, with a slight clinical information, such as history, physical examination results, increase in the 95% limit to approximately 1550 ml–1 by week 4 laboratory data, problem lists and discharge summaries. The 3M (Figure 4). A slight increase in mean monocyte count occurred Company (Minneapolis, MN, USA) approved the structure and over the first 2 weeks (Figure 5). definitions of all data points for use within the program. The data were collected from the electronic medical record, laboratory systems and case mix. Data were managed and accessed by authorized data Discussion analysts. Descriptive statistics were calculated using Statit (Corvallis, OR, USA). Means, 5 and 95% confidence intervals were used to Eosinophils are effector cells involved in allergic and nonallergic express the data. The Intermountain Healthcare institutional review inflammatory conditions. Circulating eosinophils are derived from board approved the study as a de-identified, data only investigation myelocytic progenitors within both the marrow and extramedullary not requiring written consent of the individuals. sites. After exiting the site of production and entering the blood, eosinophils circulate for approximately 1 day or so (T1/2 18 h) after which they transmigrate to tissues, primarily in the , in which they produce and .10,12 The Results physiological function of eosinophils is still somewhat enigmatic, The absolute numbers of eosinophils and monocytes (cells ml–1 but clearly they are part of a network of cells involved in , blood) were electronically retrieved from 96 162 CBCs obtained , helminthiases and inflammation. from neonates with gestational ages at birth ranging from 22 to 42 Monocytes are part of the reticuloendothelial system, which is weeks; 32 971 of these were from patients in which infection or composed of granulocytic precursors, circulating monocytes and

16000

14000

12000

10000

8000

6000

Number of Records 4000

2000

0 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Gestational Age (weeks) Figure 1 The number of records at each gestational age, from 22 to 42 weeks, represented in the subsequent studies.

Journal of Perinatology Reference ranges for eosinophils and monocytes RD Christensen et al 542

2000

1800

1600

1400

1200

1000

800 Eosinophils y = 0.3461x2- 2.9231x + 80.083 600

400

200

0 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Gestational Age Figure 2 Reference range for blood concentration of eosinophils (eosinophils per ml of blood) on the day of birth, shown according to gestational age. The lower and upper lines represent the 5 and 95% limits and the middle line represents the mean value.

3500

3000

2500

2000

y = 1.6517x2- 67.372x + 1402.2 1500 Monocytes

1000

500

0 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Gestational Age Figure 3 Reference range for blood concentration of monocytes (monocytes per ml of blood) on the day of birth, shown according to gestational age. The lower and upper lines represent the 5 and 95% limits and the middle line represents the mean value. tissue .9 Similar to other , monocytes ranges for eosinophil blood concentrations in neonates has created generally reside in the blood for <1 day (T1/2 8.4 h), after which a problem of imprecision in defining in these they transmigrate to tissues and become mononuclear neonates.13 The conditions include erythema toxicum in the , kidney, peritoneum, gastrointestinal tract or neonatorum,14,15 neonatal pustulosis16,17 and chronic reproductive tract, or become Langerhans cells, Kupffer cells, respiratory inflammation due to Chlamydia trachomatis,18 microglial cells or . respiratory syncitial virus19 or bronchopulmonary dysplasia.20–23 Several pathological conditions in neonates are associated with Other inflammatory conditions associated with eosinophilia are eosinophilic tissue infiltration, and generally these conditions are neonatal eosinophilic ,24 eosinophilic colitis,22 accompanied by blood eosinophilia. However, lacking reference subcutaneous fat with eosinophilic granules,25 a variety of

Journal of Perinatology Reference ranges for eosinophils and monocytes RD Christensen et al 543

2000

1800

1600

1400

1200

1000 y = 0.4035x2- 9.1374x + 497.22 800 Eosinophils

600

400

200

0 12345678910111213141516171819202122232425262728 Day of Life Figure 4 Reference range for blood concentration of eosinophils (eosinophils per ml of blood) during the first 28 days after birth. The lower and upper lines represent the 5 and 95% limits and the middle line represents the mean value.

3500

3000

2500

4 3 2 2000 y = 0.0128x -0.6907x + 9.9681x -9.0189x + 1076.2

1500 Monocytes

1000

500

0 12345678910111213141516171819202122232425262728 Day of Life Figure 5 Reference range for blood concentration of monocytes (monocytes per ml of blood) during the first 28 days after birth. The lower and upper lines represent the 5 and 95% limits and the middle line represents the mean value. , NEC and after erythrocyte transfusion.26 Gibson et al.27 587 neonates (5%) born at 26 to 32 weeks of gestation. The reported elevated eosinophil counts among preterm infants presence of in this cohort was associated with lower corresponding with the time when weight gain was established. mean birth weight and gestational age, , multiple Whether blood eosinophil counts are actually above the reference transfusions, albumin infusions and theophylline therapy, but not range in patients with any of these conditions can now be with maternal risk factors (pre-eclampsia, and determined. chorioamnionitis) or specific neonatal variables such as birth Monocytosis has been observed in critically ill preterm infants, asphyxia, respiratory disease and . An association with although the exact mechanisms underlying this response remain maternal steroid therapy was shown. The researchers speculated unclear. Rajadurai et al.28 detected monocytosis, which they that monocytosis represented a physiological, although immature, defined as an absolute monocyte count of >1700 ml–1,in30of response of the marrow of small premature infants to a variety of

Journal of Perinatology Reference ranges for eosinophils and monocytes RD Christensen et al 544 exogenous stimuli, including drugs and foreign protein infusions. zero is not generally within the reference range, with the exception Monocytosis has been reported in neonates with intrauterine of eosinophils in neonates of <24 weeks of gestation. Therefore, infections such as candidiasis and syphilis, although many of these neonates with a persistent eosinophil or monocyte count of zero infants had an increase in all leukocyte lineages.29,30 Monocytosis should be considered to have an abnormality. is occasionally noted in neutropenic infants.31,32 In addition to any clinical utility of these reference ranges, In our cohort, blood monocytes increased as a function of we hope that the finding of a gradual increase in blood gestational age. This is consistent with the kinetic information concentration of eosinophils and monocytes between week 22 and from fetal studies showing a maturational increase in the term will interest developmental biologists. Surely, the gradual but number of monocyte precursors. Monocytes constitute 2 to 4% of steady increase in the circulating concentrations of these cells all hemic cells during the first trimester, 3 to 7% at 30 weeks and indicates the relevance of roles that they have in human they continue to increase through the third trimester.33,34 Monocyte developmental biology. counts remain low in fetal blood until the fifth month of gestation and increase gradually once the marrow becomes the predominant site of hematopoiesis.34,35 Our reference range for monocyte Conflict of interest –1 concentrations in term infants was 300 to 3300 ml , which is The authors declare no conflict of interest. wider than the ranges reported by Kato36 (1340 to 2200 ml–1) but is comparable to the data from Xanthou37 (300 to 2100 ml–1). However, unlike the previous studies that showed highest monocyte Acknowledgments counts during the first 24 h after birth, monocyte concentrations in our cohort increased during the first 2 weeks before beginning a We thank Diane K Lambert, Intermountain Healthcare Neonatology Research for valuable assistance on this project. downward trend in the third postnatal week. The use of automated cell counters has allowed more consistency in the enumeration of monocytes; immature large granular and References neutrophil precursors at the / stage can be difficult to distinguish from monocytes on the basis of 1 Christensen RD, Henry E, Jopling J, Wiedmeier SE. The CBC: reference ranges for morphological criteria.38 In some of the early studies, enumeration neonates. Semin Perinatol 2009; 33: 3–11. 2 Jopling J, Henry E, Wiedmeier SE, Christensen RD. Reference ranges for hematocrit of these immature cells as monocytes may also have contributed to and blood hemoglobin concentration during the neonatal period: data from a the marked but transient monocytosis noted during the early multihospital healthcare system. Pediatrics 2009; 123: e333–e337. neonatal period. 3 Christensen RD, Jopling J, Henry E, Wiedmeier SE. The erythrocyte indices of neonates, In constructing neonatal reference ranges, data are generally defined using data from over 12,000 patients in a multihospital healthcare system. omitted from patients with pathology relevant to the laboratory J Perinatol 2008; 28: 24–28. parameter under study. For instance, in establishing reference 4 Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47 000 patients in a multihospital healthcare ranges for blood , patients with infections are generally system. J Perinatol 2009; 29: 130–136. eliminated, because infection sometimes results in abnormal blood 5 Wiedmeier SE, Henry D, Burnett J, Anderson T, Christensen RD. Thrombocytosis in neutrophil counts.6 In our present report, we removed patients with neonates and young infants: a report of 25 patients with platelet counts >1 000 000/ml. a discharge diagnosis of infection or NEC, but we did not remove J Perinatol; e-pub ahead of print 1 Oct 2009. those with other conditions that might influence eosinophil or 6 Schmutz N, Henry E, Jopling J, Christensen RD. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J Perinatol monocyte concentrations. For instance, it is not clear whether we 2008; 28: 275–281. should have removed data from neonates with intrauterine growth 7 Christensen RD, Henry E. Hereditary spherocytosis in neonates with hyperbilirubine- retardation, multiple anomalies or various syndromes, because it is mia. Pediatrics; e-pub ahead of print 30 Nov 2009. not known whether their eosinophil or monocyte counts are often 8 Lambert RM, Baer VL, Wiedmeier SE, Henry E, Burnett J, Christensen RD. Isolated abnormal. Now that we have a reference range with which to work, elevated blood neutrophil concentration at altitude does not require NICU admission if additional study is needed regarding groups that fall outside the appropriate reference ranges are used. J Perinatol 2009; 29: 822–825. 9 Taylor GA, Weinberg JB. Mononuclear phagocytes. In: Greer JP, Foerster J, Rodgers GM, range. We maintain that the present report is a useful step in that Paraskevas F, Glader B, Arber DA, Means Jr RT (eds). Wintrobe’s Clinical process, providing a definition of the expected values so that values Hematology.. Lippincott/Williams & Wilkins Pubs: Philadelphia, 2009, pp 252–253. higher or lower than expected can be flagged for further 10 Moqbel R, Odemuyiwa SO, Lacy P, Adamko DJ. The human eosinophil. In: Greer JP, evaluation. Foerster J, Rodgers GM, Paraskevas F, Glader B, Arber DA, Means Jr RT (eds). Before the present study, it was not clear whether abnormally Wintrobe’s Clinical Hematology.. Lippincott/Williams & Wilkins Pubs: Philadelphia, 2009, pp 214–235. low concentrations of eosinophils or monocytes could be identified. 11 Bourner G, Dhaliqui J, Summer J. Performance evaluation of the latest fully automated Specifically, it was not clear whether a result of zero per ml was hematology analyzers in a large, commercial laboratory setting; a 4-way, side-by-side 39 within the reference range. The present findings indicate that study. Lab Hematol 2005; 11: 285–297.

Journal of Perinatology Reference ranges for eosinophils and monocytes RD Christensen et al 545

12 Steinbach KH, Schick P, Trepel E, Raffler H, Do¨hrmann J, Heilgeist G et al. Estimation 25 Tajirian A, Ross R, Zeikus P, Robinson-Bostom L. Subcutaneous fat necrosis of kinetic parameters of neutrophilic eosinophilic, and basophilic granulocytes in of the newborn with eosinophilic granules. J Cutan Pathol 2007; 34: human blood. Blut 1979; 39: 27–38. 588–590. 13 Sullivan SE, Staba SL, Gersting JA, Hutson AD, Theriaque D, Christensen RD et al. 26 Juul SE, Haynes JW, McPherson RJ. Evaluation of eosinophilia in hospitalized preterm Circulating concentrations of chemokines in cord blood, neonates, and adults. Pediatr infants. J Perinatol 2005; 25: 182–188. Res 2002; 51: 653–657. 27 Gibson EL, Vaucher Y, Corrigan Jr JJ. Eosinophilia in premature infants: relationship to 14 Morgan AJ, Steen CJ, Schwartz RA, Janniger CK. Erythema toxicum neonatorum weight gain. J Pediatr 1979; 95(1): 99–101. revisited. Cutis 2009; 83: 13–16. 28 Rajadurai VS, Chambers HM, Vigneswaran R, Gardiner AA. Monocytosis in preterm 15 Marchini G, Ulfgren AK, Lore´ K, Sta˚bi B, Berggren V, Lonne-Rahm S. Erythema toxicum infants. Early Hum Dev 1992; 28: 223–229. neonatorum: an immunohistochemical analysis. Pediatr Dermatol 2001; 18: 177–187. 29 Karayalcin G, Khanijou A, Kim KY, Aballi AJ, Lanzkowsky P. Monocytosis in congenital 16 Ladrigan MK, LeBoit PE, Frieden IJ. Neonatal eosinophilic pustulosis in a 2-month old. syphilis. Am J Dis Child 1977; 131: 782–783. Pediatr Dermatol 2008; 25: 52–55. 30 Wolach B, Bogger-Goren S, Whyte R. Perinatal hematological profile of newborn 17 Asgari M, Leiferman KM, Piepkorn M, Kuechle MK. Neonatal eosinophilic pustulosis. infants with candida antenatal infections. Biol Neonate 1991; 59: 5–12. Int J Dermatol 2006; 45: 131–134. 31 Bux J, Kissel K, Nowak K, Spengel U, Mueller-Eckhardt C. Autoimmune 18 Chiang YC, Shyur SD, Huang LH, Wen TC, Yang HC, Lin MT et al. Chlamydia : clinical and laboratory studies in 143 patients. Ann Hematol 1991; 63: trachomatis pneumonia: experience in a medical center. Acta Paediatr Taiwan 2005; 249–252. 46: 284–288. 32 L’Esperance P, Brunning R, Deinard AS, Park BY, Biggar WD, Good RA. Congenital 19 Lindemans CA, Kimpen JL, Luijk B, Heidema J, Kanters D, van der Ent CK et al. neutropenia: impaired maturation with diminished stem-cell input. Birth Defects Orig Systemic eosinophil response induced by respiratory syncytial virus. Exp Immunol Artic Ser 1975; 11: 59–65. 2006; 144: 409–417. 33 Linch DC, Knott LJ, Rodeck CH, Huehns ER. Studies of circulating hemopoietic 20 Brostro¨m EB, Katz-Salamon M, Lundahl J, Hallde´n G, Winbladh B. Eosinophil progenitor cells in human fetal blood. Blood 1982; 59: 976–979. activation in preterm infants with lung disease. Acta Paediatr 2007; 96: 23–28. 34 Porcellini A, Manna A, Manna M, Talevi N, Delfini C, Moretti L et al. Ontogeny of 21 Pentiuk SP, Miller CK, Kaul A. in infants and toddlers. - progenitor cells in the human fetus. Int J Cell Cloning 1983; Dysphagia 2007; 22: 44–48. 1: 92–104. 22 Ohtsuka Y, Shimizu T, Shoji H, Kudo T, Fujii T, Wada M et al. Neonatal transient 35 Kelemen E, Janossa M. Macrophages are the first differentiated blood cells formed in eosinophilic colitis causes lower gastrointestinal bleeding in early infancy. J Pediatr human embryonic liver. Exp Hematol 1980; 8: 996–1000. Gastroenterol Nutr 2007; 44: 501–505. 36 Kato K. Leukocytes in infancy and childhood. J Pediatr 1935; 7: 7–11. 23 Yamamoto C, Kojima T, Hatrori K, Nogi S, Imamura H, Tsubura A et al. Eosinophilia 37 Xanthou M. Leucocyte blood picture in healthy full-term and premature babies during in premature infants: correlation with chronic lung disease. Acta Paediatr 1996; 85: neonatal period. Arch Dis Child 1970; 45: 242–249. 1232–1235. 38 Washburn AH. A comparison of routine and special techniques in the differentiation of 24 Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R et al. leukocytes. Am J Dis Child 1935; 50: 400–405. 14 years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr 39 Krause JR, Boggs DR. Search for in hospitalized patients with normal Gastroenterol Nutr 2009; 48(1): 30–36. blood leukocyte concentrations. Am J Hematol 1987; 24: 55–63.

Journal of Perinatology