Bronchopulmonary dysplasia

Background: Inflammation plays an important role in the pathogenesis of bronchopulmonary dysplasia (BPD), but the exact nature of this inflammatory process is incompletely understood. Older infants with established BPD have higher levels of urinary leukotriene [E.sub.4] ([LTE.sub.4]) compared to healthy infants of the same age. This suggests that cysteinyl leukotrienes may play a role in the abnormalities seen in BPD.

Objectives: To measure urinary [LTE.sub.4] levels during the first month of life in premature infants, and to determine whether there are significant differences in premature infants who develop BPD, as compared to those who do not develop BPD.

Design: Prospective, blinded, controlled study.

Setting: Neonatal ICUs of a tertiary-care university hospital.

Methods: Thirty-seven premature infants ([is less than] 33 weeks of gestational age) were enrolled prospectively at birth. Urinary [LTE.sub.4] levels were measured blinded, using a standard radioimmunoassay technique at 2 days, 7 days, and 28 days of life. At 1 month of age, infants were classified as with or without BPD, based on need for supplemental oxygen, and characteristic chest radiographs. Clinical features and urinary [LTE.sub.4] were compared between the two groups.

Results: Mean [+ or -] SD gestational age was 29 [+ or -] 2.6 weeks. None of the infants had a family history of asthma. Thirteen of 37 infants were classified as having BPD at 28 days after birth. Mean gestational age in infants who developed BPD was 27 [+ or -] 2.4 weeks, compared to 30 [+ or -] 2 weeks in infants who did not develop BPD (p [is less than] 0.05). In infants with BPD, mean urinary [LTE.sub.4] levels of urinary creatinine were 1,762 [+ or -] 2,003 pg/mg, 1,236 [+ or -] 992 pg/mg, and 5,541 [+ or -] 5,146 pg/mg at days 2, 7, and 28, respectively, compared to 1,304 [+ or -] 1,195 pg/mg, 1,158 [+ or -] 1,133 pg/mg, and 2,800 [+ or -] 2,080 pg/mg in infants without BPD. [LTE.sub.4] levels at 2 days, 7 days, and 28 days did not correlate with the subsequent development of BPD. [LTE.sub.4] levels at day 28 were significantly higher than [LTE.sub.4] levels at day 2 and day 7 in both groups, even after correcting for gestational age or birth weight (p [is less than] 0.05). There was significant inverse correlation between [LTE.sub.4] levels at day 2 with gestational age and birth weight (p [is less than] 0.05). All 13 infants with BPD received steroid pulses, compared to 3 of 26 infants without BPD. Gestational age and use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) were significantly associated with each other and with the subsequent development of BPD.

Conclusion: Urinary [LTE.sub.4] levels measured on the second day of life in very-low-birth-weight infants inversely correlate with gestational age and birth weight. Urinary [LTE.sub.4] levels may reflect lung injury and/or inflammation in premature infants, not necessarily related to BPD as it is presently defined. (CHEST 2001; 119:1749-1754)

Key words: bronchopulmonary dysplasia; infants; leukotrienes; prematurity

Abbreviations: BPD = bronchopulmonary dysplasia [LTE.sub.4] = leukotriene [E.sub.4]

Approximately 1% of all infants develop respiratory distress syndrome reflecting pulmonary immaturity. Among infants treated for respiratory distress syndrome in neonatal ICUs, approximately 20 to 30% will develop the most common form of chronic infant lung disease, bronchopulmonary dysplasia (BPD).[1] Approximately 7,000 new cases of BPD are diagnosed every year.[2] Among infants with BPD, there is a high rate of hospital readmission (up to 60%) and subsequent death (up to 20%), mainly from cardiopulmonary failure.[3] Although survival has improved, advances in therapy have not significantly decreased the incidence of BPD.[4,5] Prematurity, barotrauma, and oxygen toxicity contribute to the pathogenesis of BPD, but the exact mechanisms by which the neonatal lung undergoes such severe disruption in structure and function are incompletely understood. The potential role of inflammation and infection in the pathogenesis of BPD is suggested by several studies.[6-14] Some of the mechanisms implicated in the pathogenesis of BPD are imbalance of protease/antiprotease production, increased lipid mediators (platelet activating factor and leukotrienes),[15-19] abnormal cytokine production,[17-20] and immature development of the antioxidant system.[21] Inflammation is a key factor in the pathogenesis of BPD. Presently, the exact nature of the inflammatory process is not fully understood. Although neutrophils play a significant role in this inflammatory process, a number of other cells and mediators are also involved. It has been suggested that cysteinyl leukotrienes may also be involved. In a previous study,[19] urinary leukotriene [E.sub.4] ([LTE.sub.4]) levels obtained at 1 month of age from prematurely born infants with BPD were significantly increased, compared to premature infants without BPD. In another study,[18] in infants with prematurity and BPD, urinary [LTE.sub.4] levels were noted to be higher at 7 months of age, compared to control subjects with prematurity but without BPD. It is not known at what postnatal age the cysteinyl leukotriene system is activated, and what if any role it plays in the pathogenesis of BPD. We undertook this prospective study to evaluate levels of urinary [LTE.sub.4] in infants born prematurely.

MATERIALS AND METHODS

Study subjects were recruited from the Neonatal Intensive Unit at Allegheny General Hospital, Pittsburgh, PA, between November 1998 and April 1999. Total births at Allegheny General Hospital in 1999 were approximately 1,900/yr; of those, 420 infants were admitted to the Neonatal ICU and 80 of them weighed [is less than] 1,200 g. Exclusion criteria were evidence of ongoing sepsis (documented by a positive blood culture result), any history of urinary tract malformation, urinary tract infection, proteinuria [is greater than] 1+ on dipstick, renal failure, or hepatic disease. Only two infants were excluded from the study because of ongoing sepsis. Spot urine samples were collected on day 2, day 7, and day 28 of life, and urinary [LTE.sub.4] levels were assayed using a standard radioimmunoassay technique. Clinical staff caring for the infants were blinded to [LTE.sub.4] results, and the investigators performing the [LTE.sub.4] assay were blinded to the clinical status of the patients. At 1 month of age, infants were classified into two groups based on the presence or absence of BPD. The diagnosis of BPD was made if the infant was chronically oxygen dependent at 28 days of life and had characteristic radiographs of the chest at 28 days of life, with no evidence of other congenital abnormalities. Clinical features, including gestational age, prenatal and postnatal steroid pulses (dexamethasone), mode of delivery, Apgar score at 1 min and 5 min, use of surfactant, medications including diuretics and methylxanthines, and family history of asthma, were collected from hospital charts. Family history for asthma was considered positive if a physician diagnosed asthma in a sibling or parent either clinically or with the help of pulmonary function tests and if they were requiring daily maintenance asthma therapy. A history of atopic diseases other than asthma was not asked about. Clinical features and urinary [LTE.sub.4] levels were compared between the two groups.

Prenatal steroid regimen was dexamethasone, 0.5 mg/kg/d, to the mothers 24 to 48 h before delivery, using standard criteria.[22] Postnatal steroids were administered only to infants who were ventilator dependent at 7 days of age. In these infants, dexamethasone was administered at a dose of 0.25 mg/kg bid for 3 days at 10-day intervals, starting at day 7 and continuing until there was either no requirement for supplemental oxygen or assisted ventilation, or a postconceptual age of 36 weeks was attained.[23] None of the infants were receiving steroid pulses on the days of specimen (urine) collection.

All infants received standard management in the neonatal ICUs, and no medication or therapy was withheld because of this study. Urinary [LTE.sub.4] assays were performed at the Allergy and Immunology Section of Children's Hospital of Pittsburgh by a single operator blinded to patient status.

Urinary [LTE.sub.4] Analysis

Spot urine samples were collected from each subject on day 2, day 7, and day 28 of age, and stored at -2 [degrees] C to 0 [degrees] C until assayed. All samples were assayed at the same time. After thawing, samples were centrifuged at 8,000g for 10 min at 4 [degrees] C. An aliquot of the supernatant was then assayed in duplicate for [LTE.sub.4] levels using a commercially available enzyme immunoassay (Cayman Chemical; Ann Arbor, MI).[24] The lower limit of detectability of this assay was [is less than] 7.8 pg/mL, and the intra-assay and interassay variability were [is less than or equal to] 10%. Another aliquot of the supernatant was assayed in duplicate for creatinine levels using a commercially available colorimetric assay (Sigma Diagnostics; St. Louis, MO).[25] The lower limit of detectability of this assay was [is less than] 1 mg/dL, and the intra-assay and interassay variability were [is less than or equal to] 10.9%. Results are expressed at picograms of [LTE.sub.4] per milligram of creatinine.

Statistics

Intergroup and intragroup differences in urinary [LTE.sub.4] levels were analyzed using Wilcoxon rank sums. Pearson [chi square] was used to compare postnatal steroid pulses, prenatal steroids, diuretics, and theophylline between groups (infants with or without BPD). Correlation coefficients between [LTE.sub.4] levels and gestational age, birth weight, postnatal steroid pulses, prenatal steroids, diuretics, and theophylline were calculated using Spearman p correlations. Statistical significance was assumed if the p value was [is less than] 0.05. All statistical procedures were computed (SPSS version 9.0; SPSS; Chicago, IL).

RESULTS

Thirty-seven preterm infants (mean [+ or -] SD gestational age, 29 [+ or -] 2.6 weeks; mean birth weight, 1,259 [+ or -] 368 g) without evidence of intrauterine growth retardation were prospectively enrolled at birth in this study after written parental consent in accordance with the institutional review board of Allegheny General Hospital. Twenty-three infants were male. None of the infants had a family history of asthma. The mothers of 21 infants received prenatal dexamethasone. Fifteen infants required steroid (dexamethasone) pulses, 24 infants required theophylline for apnea of prematurity, and 12 infants required diuretics during the first month of life. In our cohort, there were five sets of twins, three sets of triplets, and two sets of quadruplets. In both sets of quadruplets, two of four infants developed BPD; among the three sets of triplets, only one infant had BPD; and among the five sets of twin births, three twins developed BPD.

Thirteen of 37 infants (35%) were classified as having BPD at 28 days after birth. The mean gestational age in infants who developed BPD was 27 [+ or -] 2.4 weeks, compared to 30.8 [+ or -] 2.9 in infants who did not develop BPD (p [is less than] 0.05). Mean birth weight in infants who developed BPD was 1,041 [+ or -] 284 g, compared to 1,377 [+ or -] 358 g in infants who did not develop BPD (p [is less than] 0.05). All 13 infants with BPD required steroid pulses, compared to 3 of 26 infants without BPD. Gestational age, use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) were significantly associated with each other and with subsequent development of BPD (Table 1).

Mean urinary [LTE.sub.4] levels of urinary creatinine were 1,465 [+ or -] 1,516 pg/mg, 1,184 [+ or -] 1,074 pg/mg, and 4,171 [+ or -] 4,060 pg/mg at days 2, 7, and 28, respectively. Mean urinary [LTE.sub.4] levels of urinary creatinine at day 28 were significantly higher when compared to mean urinary [LTE.sub.4] levels of urinary creatinine at day 2 or day 7, even after controlling for gestational age or birth weight (p [is less than] 0.05; Table 2). In infants with BPD, there was a trend, although not significant, toward higher mean urinary [LTE.sub.4] levels at day 2, day 7, or day 28, compared to infants without BPD (Fig 1), but the trend was lost after controlling for gestational age or birth weight. Gestational age and birth weight were inversely correlated with high [LTE.sub.4] levels at day 2 (r = -0.47, p = 0.003 for each) and at day 28 (r = -0.70, p = 0.001 and r = -0.79, p [is less than] 0.001, respectively). There was no association between [LTE.sub.4] levels at day 2, day 7, or day 28 with gender, steroid use by mothers before delivery, postnatal use of steroid pulses, diuretics, or theophylline.

[GRAPH OMITTED]

After controlling for gestational age or birth weight, urinary [LTE.sub.4] levels (in picograms per milligram of urinary creatinine, or absolute values in picograms) at day 2, day 7, or day 28 were not related to subsequent development of BPD.

DISCUSSION

Leukotriene [C.sub.4] and leukotriene [D.sub.4] are precursors of [LTE.sub.4], and are important mediators in the peptidoleukotriene pathway and cause bronchoconstriction, mucus production, and edema in the lungs.[15] Approximately 3 to 13% of [LTE.sub.4] formed in the lung is excreted in the urine.[26,27] In adults and children, increased urinary [LTE.sub.4] levels are observed in severe inflammatory lung disorders, such as asthma, cystic fibrosis, and ARDS.[28-22] Inflammation may play a key role in the pathogenesis of chronic lung disease of infancy, and previous work[16-18] has suggested leukotrienes have a role. It is not clear at what postnatal age the leukotriene system is activated, and if leukotriene pathway activation is specific to BPD or is a nonspecific inflammatory response secondary to lung injury because of prematurity and necessary therapies.

Normal values of [LTE.sub.4] levels in normal and asthmatic children and adults have been established and have consistently shown that urinary [LTE.sub.4] levels in normal children and adults are [is less than] 100 pg/mg creatinine.[28,32-35] Previously, it was suggested that urinary [LTE.sub.4] levels in premature infants with BPD are higher than urinary [LTE.sub.4] levels in normal children and adults, and were comparable with [LTE.sub.4] levels in adults and children with asthma.[19] Our results are similar to the study by Davidson et al,[19] but unlike their study, we were not able to correlate increased urinary [LTE.sub.4] levels with BPD. High [LTE.sub.4] levels in our study were inversely correlated with gestational age and weight at birth, but were not a useful tool to identify premature infants at risk for developing BPD. In their study, Davidson et al[19] had 34 neonates; our study had 37 neonates, including five sets of twins, three sets of triplets, and two sets of quadruplets, and the total number of families in our study was 22. Fewer families may have affected our results. In that study,[19] the BPD group had significantly lower mean gestational ages and birth weights, and were more premature. They also suffered from more severe BPD, as reflected by most of them requiring mechanical ventilation and higher oxygen requirements compared to control subjects. These factors might have contributed to significant differences in mean urinary [LTE.sub.4] levels between the groups in their study. Studies with larger numbers and similar patient groups are needed. Davidson et al[19] also noted significant reduction in urinary [LTE.sub.4] levels in patients with BPD after 5 days of IV dexamethasone treatment (in our study, although no one was receiving postnatal steroid pulse on the day of sample collection, 12 of 13 infants in the BPD group required postnatal steroid pulses compared to only 3 of 24 infants in the group without BPD). Steroids may exert anti-inflammatory effects for several days, and [LTE.sub.4] levels on day 28 in the BPD group may be masked because of steroids (none of the infants were receiving steroid pulse during the first week of life).

Nickerson and Taussig[36] suggested genetic or familial factors in the development of BPD, and noted a higher incidence of physician-diagnosed asthma in first-degree or second-degree relatives of premature infants who developed BPD, compared to premature infants without BPD. They suggested that a genetic predisposition for airway reactivity might contribute to the development and/or progression of BPD. Whether there is a genetic predisposition to develop BPD is still unresolved; recently, Hagan and colleagues[37] noted that a family history of asthma may worsen BPD, but is likely not a causal factor. In their study,[37] a family history of asthma was associated with longer supplementation of oxygen therapy only in very preterm infants with BPD. Bertrand et al[38] noted a higher incidence of bronchial hyperresponsiveness, measured by a histamine inhalation test, in preterm infants and their mothers, compared to term infants and their mothers. Follow-up studies[39] done in later childhood have found a greater-than-expected incidence of bronchial hyperresponsiveness in former premature infants than in term-born infants in general. Evans and coworkers[40] also noted an association of a family history of asthma and the clinical diagnosis of asthma between ages of 2 to 5 years in former preterm infants with or without BPD. In a follow-up study, Schauer et al[41] measured leukotriene [C.sub.4] generated by eosinophils in nonatopic prematurely born children (ages, 6 to 9 years) and compared them to healthy control subjects and children with asthma. They noted that eosinophils from the formerly preterm infants with significant bronchial hyperreactivity generated significantly higher amounts of leukotriene [C.sub.4] than normal control subjects and prematurely born children without bronchial hyperreactivity. Levels of leukotriene [C.sub.4] in that group were comparable to levels from the children with asthma. In their study, increased generation of leukotrienes correlated with bronchial hyperreactivity, but not perinatal history. In our study, which was done prospectively, [LTE.sub.4] levels were measured during the first month of life, and levels were higher than reported levels for term infants and were comparable to levels reported in the children and adults with asthma. We did not look for bronchial hyperreactivity in our group, but the absence of a family history of asthma in our patients makes it difficult to attribute high [LTE.sub.4] levels to genetic or familial predisposition for asthma.

Correlation of clinical measurements such as gestational age, birth weight, use of postnatal steroid pulses, diuretics, and theophylline (for apnea of prematurity) with subsequent development of BPD suggests that infants who subsequently develop BPD had a stormy neonatal period, compared to infants who did not develop BPD. This was also noted by other investigators.[19] [LTE.sub.4] excretion in early neonatal life may be related to the degree of prematurity and associated lung injury and inflammation, and may not be an adequate predictor of the subsequent development of BPD. It is also not clear what role leukotrienes might have on lung dysfunction as these infants grow. Long-term follow-up studies are needed because it is possible that prematurely born infants who continue to have recurrent respiratory problems in preschool and early childhood years may have persistence of high [LTE.sub.4].

ACKNOWLEDGMENT: We thank Asha Patel, MS, of the Allergy and Immunology Laboratory at Pittsburgh Children's Hospital, for performing [LTE.sub.4] assays, and John R. Hayes, PhD, at the Columbus Children's Hospital, for statistical help.

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(*) From the Division of Pulmonary Medicine (Drs. Sheikh and McCoy), Department of Pediatrics, Columbus Children's Hospital, Ohio State University, Columbus, OH; the Division of Neonatology (Drs. Null and Guthrie), Department of Pediatrics, Allegheny General Hospital, Pittsburgh, PA; and the Section of Allergy and Clinical Immunology (Drs. Gentile and Skoner, and Ms. Bimle), Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA.

Manuscript received February 28, 2000; revision accepted September 6, 2000.

Correspondence to: Shahid Sheikh, MD, Assistant Professor of Pediatrics, Ohio State University, Section of Pulmonary Medicine, Department of Pediatrics, Columbus Children's Hospital, ED 434, 700 Children's Dr, Columbus, OH 43205; e-mail: SheikhS@Pediatrics.ohio-state.edu

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