Publications by authors named "Robert L Schelonka"

51 Publications

Single-Examination Risk Prediction of Severe Retinopathy of Prematurity.

Pediatrics 2021 Nov 23. Epub 2021 Nov 23.

Departments of Ophthalmology.

Background And Objectives: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Screening and treatment reduces this risk, but requires multiple examinations of infants, most of whom will not develop severe disease. Previous work has suggested that artificial intelligence may be able to detect incident severe disease (treatment-requiring retinopathy of prematurity [TR-ROP]) before clinical diagnosis. We aimed to build a risk model that combined artificial intelligence with clinical demographics to reduce the number of examinations without missing cases of TR-ROP.

Methods: Infants undergoing routine ROP screening examinations (1579 total eyes, 190 with TR-ROP) were recruited from 8 North American study centers. A vascular severity score (VSS) was derived from retinal fundus images obtained at 32 to 33 weeks' postmenstrual age. Seven ElasticNet logistic regression models were trained on all combinations of birth weight, gestational age, and VSS. The area under the precision-recall curve was used to identify the highest-performing model.

Results: The gestational age + VSS model had the highest performance (mean ± SD area under the precision-recall curve: 0.35 ± 0.11). On 2 different test data sets (n = 444 and n = 132), sensitivity was 100% (positive predictive value: 28.1% and 22.6%) and specificity was 48.9% and 80.8% (negative predictive value: 100.0%).

Conclusions: Using a single examination, this model identified all infants who developed TR-ROP, on average, >1 month before diagnosis with moderate to high specificity. This approach could lead to earlier identification of incident severe ROP, reducing late diagnosis and treatment while simultaneously reducing the number of ROP examinations and unnecessary physiologic stress for low-risk infants.
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http://dx.doi.org/10.1542/peds.2021-051772DOI Listing
November 2021

Multivariable predictive models of death or neurodevelopmental impairment among extremely low birth weight infants using heart rate characteristics.

J Pediatr 2021 Nov 16. Epub 2021 Nov 16.

Department of Pediatrics, Division of Neonatology, Oregon Health and Science University, Portland, OR.

Objective: We hypothesized that a cumulative heart rate characteristics (HRC) index in real-time throughout the NICU hospitalization, alone or combined with birth demographics and clinical characteristics, can predict a composite outcome of death or neurodevelopmental impairment (NDI).

Study Design: We performed a retrospective analysis utilizing data from extremely low birth weight infants who were monitored for heart rate characteristics during neonatal intensive care. Surviving infants were assessed for NDI at 18-22 months. Multivariable predictive modeling of subsequent death or NDI using logistic regression, cross-validation with repeats, and step-wise feature elimination was performed each postnatal day through day 60.

Results: Among the 598 study participants, infants with the composite outcome of death or moderate-to-severe NDI had higher mean HRC scores during their stay in the NICU (3.1 ± 1.8 versus 1.3 ± 0.8, p<0.001). Predictive models for subsequent death or NDI were consistently higher when cumulative mean HRC score (cmHRC) was included as a predictor variable. A parsimonious model including birth weight, sex, ventilatory status, and cmHRC had a cross-validated ROC as high as 0.84 on days 4, 5, 6, and 8 and as low as 0.78 on days 50-52 and 56-58 to predict subsequent death or NDI.

Conclusion: In extremely low birth weight infants, higher mean HRC scores throughout their stay in the NICU were associated with a higher risk of the composite outcome of death or NDI.
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http://dx.doi.org/10.1016/j.jpeds.2021.11.026DOI Listing
November 2021

Heart rate characteristics monitoring and reduction in mortality or neurodevelopmental impairment in extremely low birthweight infants with sepsis.

Early Hum Dev 2021 Aug 4;159:105419. Epub 2021 Jul 4.

Department of Pediatrics, Division of Neonatology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239-3098, United States of America. Electronic address:

We questioned whether a heart rate characteristics (HRC) sepsis risk score displayed to clinicians would modify 18-22 month neurodevelopmental outcomes for extremely low birthweight infants who develop sepsis. Infants allocated to HRC display with sepsis had a 12% absolute reduction in the composite outcome of death or neurodevelopmental impairment. TRIAL REGISTRATION: NCT00307333.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105419DOI Listing
August 2021

Preimmune Control of the Variance of TCR CDR-B3: Insights Gained From Germline Replacement of a TCR Dβ Gene Segment With an Ig D Gene Segment.

Front Immunol 2020 11;11:2079. Epub 2020 Sep 11.

Division of Clinical Immunology and Rheumatology, Department of Medicine, Microbiology, and Genetics, The University of Alabama at Birmingham, Birmingham, AL, United States.

We have previously shown that the sequence of the immunoglobulin diversity gene segment (D ) helps dictate the structure and composition of complementarity determining region 3 of the immunoglobulin heavy chain (CDR-H3). In order to test the role of germline D sequence on the diversity of the preimmune TCRβ repertoire of T cells, we generated a mouse with a mutant TCRβ DJC locus wherein the Dβ2-Jβ2 gene segment cluster was deleted and the remaining diversity gene segment, Dβ1 (IMGT:TRDB1), was replaced with DSP2.3 (IMGT:IGHD2-02), a commonly used B cell immunoglobulin D gene segment. Crystallographic studies have shown that the length and thus structure of TCR CDR-B3 places amino acids at the tip of CDR-B3 in a position to directly interact with peptide bound to an MHC molecule. The length distribution of complementarity determining region 3 of the T cell receptor beta chain (CDR-B3) has been proposed to be restricted largely by MHC-specific selection, disfavoring CDR-B3 that are too long or too short. Here we show that the mechanism of control of CDR-B3 length depends on the Dβ sequence, which in turn dictates exonucleolytic nibbling. By contrast, the extent of N addition and the variance of created CDR3 lengths are regulated by the cell of origin, the thymocyte. We found that the sequence of the D and control of N addition collaborate to bias the distribution of CDR-B3 lengths in the pre-immune TCR repertoire and to focus the diversity provided by N addition and the sequence of the D on that portion of CDR-B3 that is most likely to interact with the peptide that is bound to the presenting MHC.
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http://dx.doi.org/10.3389/fimmu.2020.02079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518465PMC
May 2021

Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial.

J Pediatr 2020 04 4;219:48-53. Epub 2020 Feb 4.

Department of Pediatrics, University of North Carolina, Chapel Hill, NC.

Objective: To test whether the composite outcome of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age for infants ≤1000 g at birth is decreased by continuous monitoring of heart rate characteristics during neonatal intensive care.

Study Design: We studied a subset of participants enrolled in a multicenter randomized trial of heart rate characteristics monitoring. Survivors were evaluated at 18-22 months corrected age with a standardized neurologic examination and the Bayley Scales of Infant Development-III (BSID-III). NDI was defined as Gross Motor Function Classification System of >2 (moderate or severe cerebral palsy), BSID-III language or cognitive scores of <70, severe bilateral hearing impairment, and/or bilateral blindness.

Results: The composite outcome, death or NDI, was obtained for 628 of 884 study infants (72%). The prevalence of this outcome was 44.4% (136/306) among controls (infants randomized to heart rate characteristics monitored but not displayed) and 38.9% (125/322) among infants randomized to heart rate characteristics monitoring displayed (relative risk, 0.87; 95% CI, 0.73-1.05; P = .17). Mortality was reduced from 32.0% (99/307) among controls to 24.8% (81/326) among monitoring displayed infants (relative risk, 0.75; 95% CI, 0.59 to 0.97; P = .028). The composite outcomes of death or severe CP and death or mildly low Bayley cognitive score occurred less frequently in the displayed group (P < .05).

Conclusions: We found no difference in the composite outcome of death or NDI for extremely preterm infants whose heart rate characteristics were and were not displayed during neonatal intensive care. Two outcomes that included mortality or a specific NDI were less frequent in the displayed group.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096280PMC
April 2020

A neonatal nonhuman primate model of gestational Zika virus infection with evidence of microencephaly, seizures and cardiomyopathy.

PLoS One 2020 14;15(1):e0227676. Epub 2020 Jan 14.

Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon, United States of America.

Zika virus infection during pregnancy is associated with miscarriage and with a broad spectrum of fetal and neonatal developmental abnormalities collectively known as congenital Zika syndrome (CZS). Symptomology of CZS includes malformations of the brain and skull, neurodevelopmental delay, seizures, joint contractures, hearing loss and visual impairment. Previous studies of Zika virus in pregnant rhesus macaques (Macaca mulatta) have described injury to the developing fetus and pregnancy loss, but neonatal outcomes following fetal Zika virus exposure have yet to be characterized in nonhuman primates. Herein we describe the presentation of rhesus macaque neonates with a spectrum of clinical outcomes, including one infant with CZS-like symptoms including cardiomyopathy, motor delay and seizure activity following maternal infection with Zika virus during the first trimester of pregnancy. Further characterization of this neonatal nonhuman primate model of gestational Zika virus infection will provide opportunities to evaluate the efficacy of pre- and postnatal therapeutics for gestational Zika virus infection and CZS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227676PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959612PMC
April 2020

Meningitis, urinary tract, and bloodstream infections in very low birth weight infants enrolled in a heart rate characteristics monitoring trial.

Pediatr Res 2020 06 4;87(7):1226-1230. Epub 2019 Dec 4.

University of Virginia, Charlottesville, VA, USA.

Background: Displaying heart rate characteristic (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial). The aim of this study was to test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI.

Methods: Blood, urine, and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2989 VLBW infants. The HRC index was analyzed 12 h prior to positive cultures compared to 36 h prior, using paired signed-rank tests.

Results: UTI, meningitis, and BSI were diagnosed in 10%, 2%, and 24% of infants, respectively. The mean hourly HRC index was significantly higher 12 h prior to diagnosis of UTI and BSI compared to 36 h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p < 0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis.

Conclusions: In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24-h period prior to diagnosis of UTI and BSI but not meningitis.
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http://dx.doi.org/10.1038/s41390-019-0701-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255929PMC
June 2020

The Effect of Extended Continuous Positive Airway Pressure on Changes in Lung Volumes in Stable Premature Infants: A Randomized Controlled Trial.

J Pediatr 2020 02 10;217:66-72.e1. Epub 2019 Sep 10.

Division of Neonatology, Department of Pediatrics, Oregon Health & Science University, Portland, OR. Electronic address:

Objective: To compare changes in lung volumes, as measured by functional residual capacity (FRC), through to discharge in stable infants randomized to 2 weeks of extended continuous positive airway pressure CPAP (eCPAP) vs CPAP discontinuation (dCPAP).

Study Design: Infants born at ≤32 weeks of gestation requiring ≥24 hours of CPAP were randomized to 2 weeks of eCPAP vs dCPAP when meeting CPAP stability criteria. FRC was measured with the nitrogen washout technique. Infants were stratified by gestational age (<28 and ≥ 28 weeks) and twin gestation. A linear mixed-effects model was used to evaluate the change in FRC between the 2 groups. Data were analyzed blinded to treatment group allocation.

Results: Fifty infants were randomized with 6 excluded, for a total of 44 infants. Baseline characteristics were similar in the 2 groups. The infants randomized to eCPAP vs dCPAP had a greater increase in FRC from randomization through 2 weeks (12.6 mL vs 6.4 mL; adjusted 95% CI, 0.78-13.47; P = .03) and from randomization through discharge (27.2 mL vs 17.1 mL; adjusted 95% CI, 2.61-17.59; P = .01).

Conclusions: Premature infants randomized to eCPAP had a significantly greater increase in FRC through discharge compared with those randomized to dCPAP. An increased change in FRC may lead to improved respiratory health.

Trial Registration: ClinicalTrials.gov: NCT02249143.
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http://dx.doi.org/10.1016/j.jpeds.2019.07.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986570PMC
February 2020

Automated neutrophil cell counts had a limited ability to predict sepsis but that improved from 7 days of age.

Acta Paediatr 2019 11 6;108(11):2109-2110. Epub 2019 Sep 6.

Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.

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http://dx.doi.org/10.1111/apa.14964DOI Listing
November 2019

Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring.

J Pediatr 2018 07 24;198:162-167. Epub 2018 Apr 24.

Department of Pediatrics, The University of South Carolina School of Medicine-Greenville, Greenville, SC.

Objective: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT).

Study Design: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring.

Results: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance.

Conclusions: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants.

Trial Registration: ClinicalTrials.gov: NCT00307333.
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http://dx.doi.org/10.1016/j.jpeds.2018.02.045DOI Listing
July 2018

Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection.

Pediatr Res 2017 Aug 24;82(2):244-252. Epub 2017 May 24.

Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon.

BackgroundIntrauterine infection is a significant cause of early preterm birth. We have developed a fetal-neonatal model in the rhesus macaque to determine the impact of chronic intrauterine infection with Ureaplasma parvum on early neonatal reflexes and brain development.MethodsTime-mated, pregnant rhesus macaques were randomized to be inoculated with U. parvum (serovar 1; 10c.f.u.) or control media at ~120 days' gestational age (dGA). Neonates were delivered by elective hysterotomy at 135-147 dGA (term=167d), stabilized, and cared for in our nonhuman primate neonatal intensive care unit. Neonatal reflex behaviors were assessed from birth, and fetal and postnatal brain magnetic resonance imaging (MRI) was performed.ResultsA total of 13 preterm and 5 term macaque infants were included in the study. Ten preterm infants survived to 6 months of age. U. parvum-infected preterm neonates required more intensive respiratory support than did control infants. MRI studies suggested a potential perturbation of brain growth and white matter maturation with exposure to intra-amniotic infection.ConclusionWe have demonstrated the feasibility of longitudinal fetal-neonatal studies in the preterm rhesus macaque after chronic intrauterine infection. Future studies will examine long-term neurobehavioral outcomes, cognitive development, neuropathology, and in vivo brain imaging to determine the safety of antenatal antibiotic treatment for intrauterine infection.
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http://dx.doi.org/10.1038/pr.2017.57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552412PMC
August 2017

Alterations in B cell development, CDR-H3 repertoire and dsDNA-binding antibody production among C57BL/6 ΔD-iD mice congenic for the lupus susceptibility loci sle1, sle2 or sle3.

Autoimmunity 2017 Feb;50(1):42-51

a Department of Medicine , University of Alabama at Birmingham , Birmingham , AL , USA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that reflects a failure to block the production of self-reactive antibodies, especially those that bind double-stranded DNA (dsDNA). Backcrossing the lupus-prone NZM2410 genome onto C57BL/6 led to the identification of three genomic intervals, termed sle1, sle2 and sle3, which are associated with lupus susceptibility. We previously generated a C57BL/6 strain congenic for an immunoglobulin D locus (ΔD-iD) that enriches for arginine at dsDNA-binding positions. We individually introduced the ΔD-iD allele into the three sle strains to test whether one or more of these susceptibility loci could affect the developmental fate of B cells bearing arginine-enriched CDR-H3s, the CDR-H3 repertoire created by the D and the prevalence of dsDNA-binding antibodies. We found that the combination of the ΔD-iD allele and the sle1 locus led to a decrease in mature, recirculating B cell numbers and an increase in marginal zone cell numbers while maintaining a highly charged CDR-H3 repertoire. ΔD-iD and sle2 had no effect on peripheral B cell numbers, but the CDR-H3 repertoire was partially normalized. ΔD-iD and sle3 led to an increase in marginal zone B cell numbers, with some normalization of hydrophobicity. Mice with ΔD-iD combined with either sle1 or sle3 had increased production of dsDNA-binding IgM and IgG by 12 months of age. These findings indicate that the peripheral CDR-H3 repertoire can be categorically manipulated by the effects of nonimmunoglobulin genes.
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http://dx.doi.org/10.1080/08916934.2016.1272597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551388PMC
February 2017

Violation of an evolutionarily conserved immunoglobulin diversity gene sequence preference promotes production of dsDNA-specific IgG antibodies.

PLoS One 2015 23;10(2):e0118171. Epub 2015 Feb 23.

Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Variability in the developing antibody repertoire is focused on the third complementarity determining region of the H chain (CDR-H3), which lies at the center of the antigen binding site where it often plays a decisive role in antigen binding. The power of VDJ recombination and N nucleotide addition has led to the common conception that the sequence of CDR-H3 is unrestricted in its variability and random in its composition. Under this view, the immune response is solely controlled by somatic positive and negative clonal selection mechanisms that act on individual B cells to promote production of protective antibodies and prevent the production of self-reactive antibodies. This concept of a repertoire of random antigen binding sites is inconsistent with the observation that diversity (DH) gene segment sequence content by reading frame (RF) is evolutionarily conserved, creating biases in the prevalence and distribution of individual amino acids in CDR-H3. For example, arginine, which is often found in the CDR-H3 of dsDNA binding autoantibodies, is under-represented in the commonly used DH RFs rearranged by deletion, but is a frequent component of rarely used inverted RF1 (iRF1), which is rearranged by inversion. To determine the effect of altering this germline bias in DH gene segment sequence on autoantibody production, we generated mice that by genetic manipulation are forced to utilize an iRF1 sequence encoding two arginines. Over a one year period we collected serial serum samples from these unimmunized, specific pathogen-free mice and found that more than one-fifth of them contained elevated levels of dsDNA-binding IgG, but not IgM; whereas mice with a wild type DH sequence did not. Thus, germline bias against the use of arginine enriched DH sequence helps to reduce the likelihood of producing self-reactive antibodies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118171PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338297PMC
November 2015

Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants.

Pediatr Res 2014 Jul 14;76(1):100-8. Epub 2014 Apr 14.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Background: The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period.

Methods: Data on 104 extremely-low-birth-weight infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21.

Results: Male gender, non-Caucasian/non-African American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2 levels, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand-2, macrophage inflammatory protein-1β/CC-motif ligand-3, and C-reactive protein.

Conclusion: Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.
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http://dx.doi.org/10.1038/pr.2014.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062583PMC
July 2014

Immunogenicity of Haemophilus influenzae type b protein conjugate vaccines in very low birth weight infants.

Pediatr Infect Dis J 2013 Dec;32(12):1400-2

Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY Spotsylvania Regional Medical Center, Fredericksburg, VA Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, NC Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX Wake Forest University School of Medicine, Winston-Salem, NC Division of Neonatology, Oregon Health Sciences University, Portland, OR Department of Pediatrics, Wayne State University, Detroit, MI University of Miami Miller School of Medicine, Miami, FL Department of Pediatrics, Duke University, Durham, NC Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, CA Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, RI Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL Rochester General Hospital, Rochester, NY Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, MD Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1097/01.inf.0000437263.04493.7cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960569PMC
December 2013

Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial.

Pediatr Res 2013 Nov 13;74(5):570-5. Epub 2013 Aug 13.

Department of Pediatrics, University of Virginia, Charlottesville, Virginia.

Background: Abnormal heart rate characteristics (HRC) wax and wane in early stages of culture-positive, late-onset septicemia (LOS) in patients in the neonatal intensive care unit (NICU). Continuously monitoring an HRC index leads to a reduction in mortality among very low birth weight (VLBW) infants. We hypothesized that the reduction in mortality was due to a decrease in septicemia-associated mortality.

Methods: This is a secondary analysis of clinical and HRC data from 2,989 VLBW infants enrolled in a randomized clinical trial of HRC monitoring in nine NICUs from 2004 to 2010.

Results: LOS was diagnosed 974 times in 700 patients, and the incidence and distribution of organisms were similar in HRC display and nondisplay groups. Mortality within 30 d of LOS was lower in the HRC display as compared with the nondisplay group (11.8 vs. 19.6%; relative risk: 0.61; 95% confidence interval: 0.43, 0.87; P < 0.01), but mortality reduction was not statistically significant for patients without LOS. There were fewer large, abrupt increases in the HRC index in the days leading up to LOS diagnosis in infants whose HRC index was displayed.

Conclusion: Continuous HRC monitoring is associated with a lower septicemia-associated mortality in VLBW infants, possibly due to diagnosis earlier in the course of illness.
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http://dx.doi.org/10.1038/pr.2013.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026205PMC
November 2013

Recirculating bone marrow B cells in C57BL/6 mice are more tolerant of highly hydrophobic and highly charged CDR-H3s than those in BALB/c mice.

Eur J Immunol 2013 Mar 18;43(3):629-40. Epub 2013 Jan 18.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.

To test whether mechanisms controlling the range of diversity of the developing antibody repertoire in C57BL/6 mice (IgH(b)) operate similarly to those identified in BALB/c mice (IgH(a)), we compared the sequences of VH 7183-containing H-chain transcripts from sorted adult bone marrow C57BL/6 B-cell subsets with those previously obtained from BALB/c mice. Patterns of VDJ gene segment utilization and CDR-H3 amino acid composition, charge, and average length in C57BL/6 pro-B cells were similar, although not identical, to BALB/c pro-B cells. However, C57BL/6 mature, recirculating B cells failed to demonstrate the reduction in the use of VH81X and the narrowing in the range of variance of CDR-H3 hydrophobicity that characterizes B-cell maturation in BALB/c mice. To further test the ability of the C57BL/6 strain to discard B cells expressing highly charged CDR-H3s, we introduced a mutant IgH(a) DH allele that forces use of arginine, asparagine, and histidine. Unlike BALB/c mice, C57BL/6 mice congenic for the charged DH maintained normal numbers of mature, recirculating B cells that were enriched for charged CDR-H3s. Together these findings indicate that the mature C57BL/6 B-cell pool permits expression of immunoglobulins with antigen-binding sites that are typically discarded during late-stage bone marrow B-cell development in BALB/c mice.
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http://dx.doi.org/10.1002/eji.201242936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653428PMC
March 2013

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

Clin Infect Dis 2012 Dec 5;55(11):1495-502. Epub 2012 Sep 5.

Department of Pediatrics, Duke University, Durham, North Carolina 27715, USA.

Background: Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections.

Methods: Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score.

Results: Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%.

Conclusions: Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success.

Clinical Trials Registration: NCT00621192.
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http://dx.doi.org/10.1093/cid/cis758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491861PMC
December 2012

Cytokine profiles of preterm neonates with fungal and bacterial sepsis.

Pediatr Res 2012 Aug;72(2):212-20

Department of Pediatrics, Wayne State University, Detroit, Michigan, USA.

Background: Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight (ELBW) infants, is lacking. We hypothesized that cytokine profiles in the first 21 d of life in ELBW infants with FS differ from those with bacterial sepsis (BS) or no sepsis (NS).

Methods: In a secondary analysis of the National Institute of Child Health and Human Development Cytokine study, three groups were defined-FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3 and sepsis group was explored.

Results: Of 1,066 infants, 89 had FS and 368 had BS. As compared with BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (P < 0.05). Analyses controlling for covariates showed significant group differences over time for interferon-γ (IFN-γ), interleukin (IL)-10, IL-18, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) (P < 0.05).

Conclusion: Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-β, and TNF-α in FS, BS, or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.
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http://dx.doi.org/10.1038/pr.2012.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629907PMC
August 2012

Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial.

J Pediatr 2011 Dec 24;159(6):900-6.e1. Epub 2011 Aug 24.

Department of Medicine, University of Virginia, Charlottesville, VA 22901, USA.

Objective: To test the hypothesis that heart rate characteristics (HRC) monitoring improves neonatal outcomes.

Study Design: We conducted a two-group, parallel, individually randomized controlled clinical trial of 3003 very low birth weight infants in 9 neonatal intensive care units. In one group, HRC monitoring was displayed; in the other, it was masked. The primary outcome was number of days alive and ventilator-free in the 120 days after randomization. Secondary outcomes were mortality, number of ventilator days, neonatal intensive care unit stay, and antibiotic use.

Results: The mortality rate was reduced in infants whose HRC monitoring was displayed, from 10.2% to 8.1% (hazard ratio, 0.78; 95% CI, 0.61-0.99; P = .04; number needed to monitor = 48), and there was a trend toward increased days alive and ventilator-free (95.9 of 120 days compared with 93.6 in control subjects, P = .08). The mortality benefit was concentrated in infants with a birth weight <1000 g (hazard ratio, 0.74; 95% CI, 0.57-0.95; P = .02; number needed to monitor = 23). There were no significant differences in the other outcomes.

Conclusion: HRC monitoring can reduce the mortality rate in very low birth weight infants.
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http://dx.doi.org/10.1016/j.jpeds.2011.06.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215822PMC
December 2011

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections.

Pediatr Infect Dis J 2011 Oct;30(10):844-9

Department of Pediatrics, Duke University, Durham, NC, USA.

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events.

Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM.

Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23-40) weeks and 21 (1-92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 μg/mL for 50% of the dose interval and >2 μg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5-148).

Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.
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http://dx.doi.org/10.1097/INF.0b013e31822e8b0bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173561PMC
October 2011

Absence of N addition facilitates B cell development, but impairs immune responses.

Immunogenetics 2011 Sep 10;63(9):599-609. Epub 2011 Jun 10.

Department of Pediatrics, University of Alabama at Birmingham, USA.

The programmed, stepwise acquisition of immunocompetence that marks the development of the fetal immune response proceeds during a period when both T cell receptor and immunoglobulin (Ig) repertoires exhibit reduced junctional diversity due to physiologic terminal deoxynucleotidyl transferase (TdT) insufficiency. To test the effect of N addition on humoral responses, we transplanted bone marrow from TdT-deficient (TdT(-/-)) and wild-type (TdT(+/+)) BALB/c mice into recombination activation gene 1-deficient BALB/c hosts. Mice transplanted with TdT(-/-) cells exhibited diminished humoral responses to the T-independent antigens α-1-dextran and (2,4,6-trinitrophenyl) hapten conjugated to AminoEthylCarboxymethyl-FICOLL, to the T-dependent antigens NP(19)CGG and hen egg lysozyme, and to Enterobacter cloacae, a commensal bacteria that can become an opportunistic pathogen in immature and immunocompromised hosts. An exception to this pattern of reduction was the T-independent anti-phosphorylcholine response to Streptococcus pneumoniae, which is normally dominated by the N-deficient T15 idiotype. Most of the humoral immune responses in the recipients of TdT(-/-) bone marrow were impaired, yet population of the blood with B and T cells occurred more rapidly. To further test the effect of N-deficiency on B cell and T cell population growth, transplanted TdT-sufficient and -deficient BALB/c IgM(a) and congenic TdT-sufficient CB17 IgM(b) bone marrow were placed in competition. TdT(-/-) cells demonstrated an advantage in populating the bone marrow, the spleen, and the peritoneal cavity. TdT deficiency, which characterizes fetal lymphocytes, thus appears to facilitate filling both central and peripheral lymphoid compartments, but at the cost of altered responses to a broad set of antigens.
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http://dx.doi.org/10.1007/s00251-011-0543-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181008PMC
September 2011

Fetal and neonatal morbidity and mortality following delivery after previous cesarean.

Clin Perinatol 2011 Jun;38(2):311-9

Division of Neonatology, Department of Pediatrics, Oregon Health & Science University, Mail code CDRCP, Portland, OR 97239-2998, USA.

This article examines data from a recent systematic evidence review on term deliveries conducted for the National Institutes of Health Consensus Conference sponsored by the Agency for Healthcare Research and Quality on vaginal birth after caesarean, from a meta-analysis of associated perinatal outcomes, and subsequent publications that meet stringent quality review standards. We present a summary of fetal and neonatal outcomes emphasizing information that clinicians and patients need to make decisions regarding mode of delivery after prior cesarean and look for areas where future studies may provide important insights.
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http://dx.doi.org/10.1016/j.clp.2011.03.001DOI Listing
June 2011

T cell cytokines and the risk of blood stream infection in extremely low birth weight infants.

Cytokine 2011 Feb 9;53(2):249-55. Epub 2010 Dec 9.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.

Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-γ [INF-γ], tumor necrosis factor-β [TNF-β], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.
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http://dx.doi.org/10.1016/j.cyto.2010.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042892PMC
February 2011

The CDR-H3 repertoire from TdT-deficient adult bone marrow is a close, but not exact, homologue of the CDR-H3 repertoire from perinatal liver.

J Immunol 2010 Nov 18;185(10):6075-84. Epub 2010 Oct 18.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Compared with adult bone marrow (BM), the composition of the perinatal liver CDR-3 of the Ig H chain (CDR-H3) repertoire is marked by a paucity of N nucleotides and by enrichment for use of J(H) proximal DQ52 and D(H) proximal V(H) and J(H) gene segments. To test the extent to which these differences reflect limited perinatal TdT activity versus differences in the fetal/adult environment, we used the Hardy scheme to sort fractions B-F B lineage cells from TdT-deficient BALB/c adult BM. V(H)7183-containing VDJCμ transcripts from these cells were amplified, cloned, sequenced, and compared with transcripts from wild-type perinatal liver and adult BM. The pattern of V(H)DJ(H) usage in TdT-deficient BM largely matched that of TdT-sufficient adult cells. What minor differences were detected in the pro-B cell stage tended to diminish with B cell maturation, suggesting strong environmental or Ag-driven pressure to achieve a specific range of V(H)DJ(H) usage regardless of the extent of N nucleotide addition. However, although the patterns of V(H)DJ(H) usage in the TdT-deficient B lineage cells paralleled that of wild-type adult cells, the length distribution, global amino acid composition, and charge distribution of the CDR-H3 repertoire proved to be a close, although not exact, homologue of the CDR-H3 repertoire first expressed by late pre-B cells in the TdT-insufficient perinatal liver. Thus, although differing in V(H) content, TdT-deficient mice appear to represent a good, although not perfect, model for testing the role of perinatal CDR-H3 limitations on late B cell development and Ab responses.
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http://dx.doi.org/10.4049/jimmunol.1001419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670101PMC
November 2010

The peritoneal cavity B-2 antibody repertoire appears to reflect many of the same selective pressures that shape the B-1a and B-1b repertoires.

J Immunol 2010 Nov 18;185(10):6085-95. Epub 2010 Oct 18.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

To assess the extent and nature of somatic categorical selection of CDR-3 of the Ig H chain (CDR-H3) content in peritoneal cavity (PerC) B cells, we analyzed the composition of V(H)7183DJCμ transcripts derived from sorted PerC B-1a, B-1b, and B-2 cells. We divided these sequences into those that contained N nucleotides (N(+)) and those that did not (N(-)) and then compared them with sequences cloned from sorted IgM(+)IgD(+) B cells from neonatal liver and both wild-type and TdT-deficient adult bone marrow. We found that the PerC B-1a N(-) repertoire is enriched for the signatures of CDR-H3 sequences present in neonatal liver and shares many features with the B-1b N(-) repertoire, whereas the PerC B-1a N(+), B-1b N(+), and B-2 N(+) repertoires are enriched for adult bone marrow sequence signatures. However, we also found several sequence signatures that were not shared with other mature perinatal or adult B cell subsets but were either unique or variably shared between the two or even among all three of the PerC subsets that we examined. These signatures included more sequences lacking N nucleotides in the B-2 population and an increased use of D(H) reading frame 2, which created CDR-H3s of greater average hydrophobicity. These findings provide support for both ontogenetic origin and shared Ag receptor-influenced selection as the mechanisms that shape the unique composition of the B-1a, B-1b, and B-2 repertoires. The PerC may thus serve as a general reservoir for B cells with Ag binding specificities that are uncommon in other mature compartments.
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http://dx.doi.org/10.4049/jimmunol.1001423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667605PMC
November 2010

DH and JH usage in murine fetal liver mirrors that of human fetal liver.

Immunogenetics 2010 Oct 17;62(10):653-66. Epub 2010 Aug 17.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.

In mouse and human, the regulated development of antibody repertoire diversity during ontogeny proceeds in parallel with the development of the ability to generate antibodies to an array of specific antigens. Compared to adult, the human fetal antibody repertoire limits N addition and uses specifically positioned VDJ gene segments more frequently, including V6-1 the most D(H)-proximal V(H,) DQ52, the most J(H)-proximal D(H), and J(H)2, which is D(H)-proximal. The murine fetal antibody repertoire also limits the incorporation of N nucleotides and uses its most D(H) proximal V(H), V(H)81X, more frequently. To test whether D(H) and J(H) also follow the pattern observed in human, we used the scheme of Hardy to sort B lineage cells from BALB/c fetal and neonatal liver, RT-PCR cloned and sequenced V(H)7183-containing VDJCμ transcripts, and then assessed V(H)7183-D(H)-J(H) and complementary determining region 3 of the immunoglobulin heavy chain (CDR-H3) content in comparison to the previously studied adult BALB/c mouse repertoire. Due to the deficiency in N nucleotide addition, perinatal CDR-H3s manifested a distinct pattern of amino acid usage and predicted loop structures. As in the case of adult bone marrow, we observed a focusing of CDR-H3 length and CDR-H3 loop hydrophobicity, especially in the transition from the early to late pre-B cell stage, a developmental checkpoint associated with expression of the pre-B cell receptor. However, fetal liver usage of J(H)-proximal D(H)Q52 and D(H)-proximal J(H)2 was markedly greater than that of adult bone marrow. Thus, the early pattern of D(H) and J(H) usage in mouse feta liver mirrors that of human.
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http://dx.doi.org/10.1007/s00251-010-0469-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944024PMC
October 2010

Genetic control of DH reading frame and its effect on B-cell development and antigen-specifc antibody production.

Crit Rev Immunol 2010 ;30(4):327-44

Department of Medicine, University of Alabama at Birmingham, 35294-2182, USA.

The power of the adaptive immune system to identify novel antigens depends on the ability of lymphocytes to create antigen receptors with diverse antigen-binding sites. For immunoglobulins, CDR (complementarity-determining region)-H3 lies at the center of the antigen-binding site, where it often plays a key role in antigen binding. It is created de novo by VDJ rearrangement and is thus the focus for rearrangement-dependent diversity. CDR-H3 is biased for the inclusion of tyrosine. In seeking to identify the mechanisms controlling CDR-H3 amino acid content, we observed that the coding sequence of DH gene segments demonstrate conservation of reading frame (RF)-specific sequence motifs, with RF1 enriched for tyrosine and depleted of hydrophobic and charged amino acids. Use of DH RF1 in functional VDJ transcripts is preferred from the earliest stages of B-cell development, "pushing" CDR-H3 to include specific categories of tyrosine-enriched antigen-binding sites. With development and maturation, the composition of the CDR-H3 repertoire appears to be pulled into a more refined specific range. Forcing the use of alternative DH RFs by means of gene targeting alters the expressed repertoire, enriching alternative sequence categories. This change in the repertoire variably affects antibody production and the development of specific B-cell subsets.
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http://dx.doi.org/10.1615/critrevimmunol.v30.i4.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676173PMC
September 2010

Heptavalent pneumococcal conjugate vaccine immunogenicity in very-low-birth-weight, premature infants.

Pediatr Infect Dis J 2010 Jul;29(7):600-6

University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Background: The heptavalent pneumococcal CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (< or =1500 g) infants.

Objective: To assess PCV-7 immunogenicity in very-low-birth-weight, premature infants. We hypothesized that the frequency of postvaccine antibody concentrations > or =0.15 microg/mL would vary directly with birth weight.

Methods: This was a multicenter observational study. Infants 401 to 1500 g birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 National Institute of Child Health and Human Development Neonatal Research Network centers. Infants received PCV-7 at 2, 4, and 6 months after birth and had blood drawn 4 to 6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.

Results: Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 +/- 2.2 (mean +/- standard deviation) weeks gestation and 1008 +/- 282 g birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001 to 1500 g birth weight were more likely than those 401 to 1000 g to achieve antibody concentrations > or =0.15 microg/mL against the least 2 immunogenic serotypes (6B: 96% vs. 85%, P = 0.003 and 23F: 97% vs. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw, and Caucasian race were each independently associated with antibody concentrations <0.35 microg/mL against serotypes 6B and/or 23F.

Conclusions: When compared with larger premature infants, infants weighing < or =1000 g at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.
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http://dx.doi.org/10.1097/INF.0b013e3181d264a6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949965PMC
July 2010
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