Publications by authors named "Michael W Quasney"

50 Publications

Proprotein Convertase Subtilisin/Kexin Type 9 Loss-of-Function Is Detrimental to the Juvenile Host With Septic Shock.

Crit Care Med 2020 Oct;48(10):1513-1520

Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH.

Objectives: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis. We sought to validate this association in children with septic shock and in a juvenile murine model of sepsis.

Design: Prospectively enrolled cohort of children with septic shock; experimental mice.

Setting: Seventeen participating institutions; research laboratory.

Patients And Subjects: Five-hundred twenty-two children with septic shock; juvenile (14 d old) and adult (10-14 wk) mice with constitutive proprotein convertase subtilisin/kexin type 9 null and wildtype control mice (C57BL/6).

Interventions: Proprotein convertase subtilisin/kexin type 9 single-nucleotide polymorphisms, serum proprotein convertase subtilisin/kexin type 9, and lipid profiles in patients. Cecal slurry murine model of sepsis; survival studies in juvenile and adult mice, assessment of lipoprotein fractions, bacterial burden, and inflammation in juvenile mice.

Measurements And Main Results: PCSK9 loss-of-function genetic variants were independently associated with increased odds of complicated course and mortality in children with septic shock. PCSK9, low-density lipoprotein, and high-density lipoprotein concentrations were lower among patients with complicated course relative to those without. PCSK9 concentrations negatively correlated with proinflammatory cytokine interleukin-8. Proprotein convertase subtilisin/kexin type 9 loss-of-function decreased survival in juvenile mice, but increased survival in adult mice with sepsis. PCSK9 loss-of-function resulted in low lipoproteins and decreased hepatic bacterial burden in juvenile mice.

Conclusions: In contrast to the adult host, proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. PCSK9 loss-of-function, in the context of low lipoproteins, may result in reduced hepatic bacterial clearance in the juvenile host with septic shock. Our data indicate that children should be excluded in sepsis clinical trials involving proprotein convertase subtilisin/kexin type 9 inhibitors.
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http://dx.doi.org/10.1097/CCM.0000000000004487DOI Listing
October 2020

Association of patient weight status with plasma surfactant protein D, a biomarker of alveolar epithelial injury, in children with acute respiratory failure.

Pediatr Pulmonol 2020 10 7;55(10):2730-2736. Epub 2020 Aug 7.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.

Aims And Objectives: Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission.

Methods: Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested.

Results: Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05).

Conclusions: Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.
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http://dx.doi.org/10.1002/ppul.24990DOI Listing
October 2020

Impact of Bilateral Infiltrates on Inflammatory Biomarker Levels and Clinical Outcomes of Children With Oxygenation Defect.

Crit Care Med 2020 Jun;48(6):e498-e504

Division of Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI.

Objectives: The 2015 definition for pediatric acute respiratory distress syndrome did not require the presence of bilateral infiltrates. We tested the hypothesis that pediatric patients meeting oxygenation criteria for pediatric acute respiratory distress syndrome but without bilateral infiltrates would have different inflammatory biomarker levels and clinical outcomes than those with bilateral infiltrates.

Design: Secondary analysis of a prospective cohort study.

Setting: Twenty-two PICUs.

Patients: Four-hundred forty-six patients age 2 weeks to 17 years intubated for respiratory failure with oxygenation index greater than or equal to 4 or oxygenation saturation index greater than or equal to 5 on the day of intubation or the day after.

Interventions: None.

Measurements And Main Results: Patients with bilateral infiltrates, either on the day of intubation or within the following 2 days, were compared with children who never developed bilateral infiltrates. Two analyses were performed to test 1) whether bilateral infiltrates are associated with elevated interleukin-1 receptor antagonist or interleukin-8 and 2) whether bilateral infiltrates are associated with worse clinical outcomes. Patients with bilateral infiltrates more often had a primary diagnosis of pneumonia (41% vs 28%; p = 0.02) and less often asthma (8% vs 23%; p < 0.01). After controlling for age, gender, and primary diagnosis, interleukin-1 receptor antagonist was higher on study days 1 and 2 in patients with bilateral infiltrates. There was no difference in interleukin-8 levels. After adjusting for age, gender, Pediatric Risk of Mortality score, and severity of oxygenation defect, presence of bilateral infiltrates was associated with longer duration of mechanical ventilation in survivors (hazard ratio, 0.64; 95% CI, 0.49-0.82; p < 0.01); this association was independent of primary diagnosis. Overall mortality was 9%; mortality was higher in those without bilateral infiltrates (14% vs 8%; p = 0.04).

Conclusions: Children meeting pediatric acute respiratory distress syndrome oxygenation criteria with bilateral infiltrates on chest radiograph experience a more intense early inflammatory response. Bilateral infiltrates are associated with longer time on the ventilator independent of oxygenation defect severity.
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http://dx.doi.org/10.1097/CCM.0000000000004316DOI Listing
June 2020

Surfactant Protein D Is Associated With Severe Pediatric ARDS, Prolonged Ventilation, and Death in Children With Acute Respiratory Failure.

Chest 2020 Sep 8;158(3):1027-1035. Epub 2020 Apr 8.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI. Electronic address:

Background: Elevated surfactant protein D (SP-D) is a relatively specific indicator of lung injury and is associated with both acute and chronic lung disease in adults and respiratory distress syndrome in premature infants. The relationship between plasma SP-D and lung injury in children with acute respiratory failure is unclear.

Research Question: Is plasma SP-D associated with lung injury or outcome in children with acute respiratory failure?

Study Design And Methods: This was a prospective cohort study in children 2 weeks to 17 years of age with acute respiratory failure who participated in the BALI multi-center study. Analyses were done using SP-D levels in plasma from the first sample taken on either the day of intubation or one of the following 2 days. SP-D level was measured by enzyme-linked immunosorbent assay.

Results: Plasma samples from 350 patients were used in the analysis; 233 had pediatric ARDS (PARDS). SP-D levels varied across primary diagnoses (P < .001). Elevated SP-D levels were associated with severe PARDS after adjusting for age, pediatric risk of mortality III (PRISM-III), and primary diagnosis (OR = 1.02; CI = 1.01-1.04; P = .011). Multivariable analyses also indicated that elevated SP-D levels were associated with death (OR = 1.02; CI = 1.01-1.04; P = .004), duration of mechanical ventilation (P = .012), PICU length of stay (P = .019), and highest oxygenation index (P = .040). SP-D levels also correlated with age (r = 0.16, P = .002).

Interpretation: Elevated plasma SP-D levels are associated with severe PARDS and poor outcomes in children with acute respiratory failure. Future studies will determine whether SP-D can be used to predict the degree of lung injury or response to treatment and whether SP-D is useful in identifying PARDS endotypes.
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http://dx.doi.org/10.1016/j.chest.2020.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478231PMC
September 2020

Human Metapneumovirus Infection in Hospitalized Children.

Respir Care 2020 May 11;65(5):650-657. Epub 2020 Feb 11.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.

Background: Most children are exposed to human metapneumovirus (HMPV) by the age of 5 y. This study aimed to describe the morbidity associated with HMPV infections in a cohort of children in the Midwest of the United States.

Methods: This was a retrospective 2-center cohort study including children (0-17 y old) hospitalized with HMPV infections at 2 tertiary care pediatric hospitals from 2009 to 2013. Demographics, chronic medical conditions, viral coinfections, and hospitalization characteristics, including the need for respiratory support, high-flow nasal cannula, CPAP, bi-level positive airway pressure, invasive mechanical ventilation, pediatric ICU admission, acute kidney injury (AKI), use of extracorporeal membrane oxygenation, and length of stay, were collected.

Results: In total, 131 subjects were included. Those with one or more comorbidities were older than their otherwise healthy counterparts, with a median age of 2.8 y (interquartile range [IQR] 1.1-7.0) compared to 1.3 y (IQR 0.6-2.0, < .001), respectively. Ninety-nine (75.6%) subjects required respiratory support; 72 (55.0%) subjects required nasal cannula, simple face mask, or tracheostomy mask as their maximum support. Additionally, 1 (0.8%) subject required high-flow nasal cannula, 1 (0.8%) subject required CPAP, 2 (1.5%) subjects required bi-level positive airway pressure, 15 (11.5%) subjects required invasive mechanical ventilation, 4 (3.1%) subjects required high-frequency oscillatory or jet ventilation, and 4 (3.1%) subjects required extracorporeal membrane oxygenation. Fifty-one (38.9%) subjects required pediatric ICU admission, and 16 (12.2%) subjects developed AKI. Subjects with AKI were significantly older than those without AKI at 5.4 y old (IQR 1.6-11.7) versus 1.9 y old (IQR 0.7-3.5, = .003). After controlling for the presence of at least one comorbidity and cystic fibrosis, each year increase in age led to a 16% increase in the odds of AKI ( = .01). The median length of stay for the entire cohort was 4.0 d (IQR 2.7-7.0).

Conclusions: Children hospitalized with HMPV may be at risk for AKI. Risk of HMPV-associated AKI appears to increase with age regardless of severity of respiratory illness or presence of comorbidities.
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http://dx.doi.org/10.4187/respcare.07156DOI Listing
May 2020

A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome.

Crit Care 2019 04 17;23(1):128. Epub 2019 Apr 17.

Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Dr, F6790/5243, Ann Arbor, MI, 48109, USA.

Background: The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure.

Methods: This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped.

Results: Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4-12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level.

Conclusions: When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.
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http://dx.doi.org/10.1186/s13054-019-2342-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471952PMC
April 2019

Identification of molecular signatures of cystic fibrosis disease status with plasma-based functional genomics.

Physiol Genomics 2019 01 12;51(1):27-41. Epub 2018 Dec 12.

Division of Endocrinology, Department of Pediatrics, Medical College of Wisconsin , Milwaukee, Wisconsin.

Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and the development of inflammation and progression of lung disease are not fully understood, which limits our ability to predict an individual patient's clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status with plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients ( n = 103) and unrelated, healthy controls ( n = 31). Gene expression levels were measured with an Affymetrix microarray (GeneChip Human Genome U133 Plus 2.0). Peripheral blood samples from a subset of the CF patients ( n = 40) were immunophenotyped by flow cytometry, and the data were compared with historical data for age-matched healthy controls ( n = 351). Plasma samples from another subset of CF patients ( n = 56) and healthy controls ( n = 16) were analyzed by multiplex enzyme-linked immunosorbent assay (ELISA) for numerous cytokines and chemokines. Principal component analysis and hierarchical clustering of induced transcriptional data revealed disease-specific plasma-induced PBMC profiles. Among 1,094 differentially expressed probe sets, 51 genes were associated with pancreatic sufficient status, and 224 genes were associated with infection with Pseudomonas aeruginosa. The flow cytometry and ELISA data confirmed that various immune modulators are relevant contributors to the CF molecular signature. This study provides strong evidence for distinct molecular signatures among CF patients. An understanding of these molecular signatures may lead to unique molecular markers that will enable more personalized prognoses, individualized treatment plans, and rapid monitoring of treatment response.
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http://dx.doi.org/10.1152/physiolgenomics.00109.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383551PMC
January 2019

Outcomes and Patterns of Healthcare Utilization After Hospitalization for Pediatric Critical Illness Due to Respiratory Failure.

Pediatr Crit Care Med 2019 02;20(2):120-127

Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

Objectives: To quantify home care needs, healthcare utilization, and 2-year mortality after pediatric critical illness due to respiratory failure, and evaluate the impact of new morbidity and abnormal function at hospital discharge on resource use and outcomes.

Design: Retrospective cohort study.

Setting: Quaternary care PICU.

Patients: Patients less than or equal to 18 years with respiratory failure from January 1, 2013, to December 31, 2014.

Measurements And Main Results: Patient demographics, hospitalization characteristics, and healthcare utilization were quantified and compared according to morbidity development and discharge functional status. Multivariable regression methods evaluated 2-year readmission rates and mortality by morbidity development and discharge functional status. Of 163 patients, the median age was 2.1 years (interquartile range, 0.6-10.9 yr), 61 (37.4%) had a comorbidity, and 73 (44.8%) had abnormal function at admission. Median ventilation duration was 6.0 days (interquartile range, 3.0-11.7 d), and median PICU and hospital length of stay were 8 (interquartile range, 4-15) and 14 days (interquartile range, 8-23 d), respectively. At hospital discharge, eight of 163 (4.9%) had died, and 14 of 163 (8.6%) had a new morbidity. Of the surviving 155 patients at hospital discharge, 87 (56.1%) had abnormal function, 120 (77.4%) had new medications, 24 (15.5%) had new medical devices, and 43 (27.7%) had new home care equipment. Cumulative 2-year mortality was 14 of 163 (8.6%) with six of 163 (3.7%) occurring after discharge. Within 2 years, 81 of 155 of patients (52.2%) were readmitted, often (58/81, 71.6%) to the PICU. Abnormal function at discharge was associated with elevated odds of readmission to the hospital (odds ratio, 1.49; 1.28-1.74; p < 0.0001) and PICU (odds ratio, 1.47; 1.27-1.71; p < 0.0001) within 2 years.

Conclusions: After critical illness, children have significant new healthcare burdens heretofore unrecognized. Abnormal functional status at hospital discharge was associated with increased healthcare utilization up to 2 years thereafter.
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http://dx.doi.org/10.1097/PCC.0000000000001797DOI Listing
February 2019

Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.

Pediatr Crit Care Med 2018 10;19(10):930-938

Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

Objectives: To test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1β levels or interleukin-1β response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease.

Design: Prospective cohort study.

Setting: Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622).

Subjects: Children 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease.

Measurements And Main Results: Three-hundred seventy-eight of 549 patients had pediatric acute respiratory distress syndrome; DNA and plasma were obtained from 523 of 549 and 480 of 549 patients, respectively. Plasma interleukin-1ra was highest on the day of intubation (day 0) and decreased over the subsequent 3 days (p < 0.0001). Interleukin-1ra level was higher in patients with pediatric acute respiratory distress syndrome than those without pediatric acute respiratory distress syndrome (p < 0.0001). Multivariable regression analysis of data across all days demonstrated a significant association of interleukin-1ra (odds ratio, 1.30; 95% CI, 1.10-1.52; p = 0.002) and day (p < 0.05) with pediatric acute respiratory distress syndrome, independent of age and Pediatric Risk of Mortality-III score. Analysis on individual days indicated that plasma interleukin-1ra levels were associated with pediatric acute respiratory distress syndrome on days 0 and 2, independent of age and Pediatric Risk of Mortality-III score (p = 0.04 and 0.003, respectively), however did not quite reach significance on days 1 and 3 (p = 0.06 and 0.07, respectively). Interleukin-1ra was independently associated with mortality on day 1 (p = 0.02). Interleukin-1ra also correlated with length of mechanical ventilation, measures of oxygenation, and PICU length of stay. No genetic variants were associated with pediatric acute respiratory distress syndrome.

Conclusions: Plasma interleukin-1ra is associated with pediatric acute respiratory distress syndrome, PICU length of stay, length of mechanical ventilation, and mortality in children with acute respiratory failure requiring mechanical ventilation.
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http://dx.doi.org/10.1097/PCC.0000000000001680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170680PMC
October 2018

Interleukin-1 Receptor Antagonist Is Associated With Pediatric Acute Respiratory Distress Syndrome and Worse Outcomes in Children With Acute Respiratory Failure.

Pediatr Crit Care Med 2018 10;19(10):930-938

Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

Objectives: To test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1β levels or interleukin-1β response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease.

Design: Prospective cohort study.

Setting: Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622).

Subjects: Children 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease.

Measurements And Main Results: Three-hundred seventy-eight of 549 patients had pediatric acute respiratory distress syndrome; DNA and plasma were obtained from 523 of 549 and 480 of 549 patients, respectively. Plasma interleukin-1ra was highest on the day of intubation (day 0) and decreased over the subsequent 3 days (p < 0.0001). Interleukin-1ra level was higher in patients with pediatric acute respiratory distress syndrome than those without pediatric acute respiratory distress syndrome (p < 0.0001). Multivariable regression analysis of data across all days demonstrated a significant association of interleukin-1ra (odds ratio, 1.30; 95% CI, 1.10-1.52; p = 0.002) and day (p < 0.05) with pediatric acute respiratory distress syndrome, independent of age and Pediatric Risk of Mortality-III score. Analysis on individual days indicated that plasma interleukin-1ra levels were associated with pediatric acute respiratory distress syndrome on days 0 and 2, independent of age and Pediatric Risk of Mortality-III score (p = 0.04 and 0.003, respectively), however did not quite reach significance on days 1 and 3 (p = 0.06 and 0.07, respectively). Interleukin-1ra was independently associated with mortality on day 1 (p = 0.02). Interleukin-1ra also correlated with length of mechanical ventilation, measures of oxygenation, and PICU length of stay. No genetic variants were associated with pediatric acute respiratory distress syndrome.

Conclusions: Plasma interleukin-1ra is associated with pediatric acute respiratory distress syndrome, PICU length of stay, length of mechanical ventilation, and mortality in children with acute respiratory failure requiring mechanical ventilation.
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http://dx.doi.org/10.1097/PCC.0000000000001680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170680PMC
October 2018

Association of polymorphisms in genes of factors involved in regulation of splicing of cystic fibrosis transmembrane conductance regulator mRNA with acute respiratory distress syndrome in children with pneumonia.

Crit Care 2016 09 5;20:281. Epub 2016 Sep 5.

Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Dr, SPC 5243, Ann Arbor, MI, 48109-5243, USA.

Background: Previous work has demonstrated a strong association between lung injury in African American children with pneumonia and a polymorphic (TG)mTn region in cystic fibrosis transmembrane conductance (CFTR) involved in the generation of a nonfunctional CFTR protein lacking exon 9. A number of splicing factors that regulate the inclusion/exclusion of exon 9 have been identified. The objective of this study was to determine whether genetic variants in these splicing factors were associated with acute respiratory distress syndrome (ARDS) in children with pneumonia.

Methods: This is a prospective cohort genetic association study of lung injury in African American and non-Hispanic Caucasian children with community-acquired pneumonia evaluated in the emergency department or admitted to the hospital. Linkage-disequilibrium-tag single nucleotide polymorphisms (LD-tag SNPs) in genes of the following splicing factors (followed by gene name) involved in exon 9 skipping PTB1 (PTBP1), SRp40 (SFRS1), SR2/ASF (SFRS5), TDP-43 (TARDBP), TIA-1 (TIA1), and U2AF(65) (U2AF2) were genotyped. SNPs in the gene of the splicing factor CELF2 (CELF2) were selected by conservation score. Multivariable analysis was used to examine association between genotypes and ARDS.

Results: The African American cohort (n = 474) had 29 children with ARDS and the non-Hispanic Caucasian cohort (n = 304) had 32 children with ARDS. In the African American group multivariable analysis indicated that three variants in CELF2, rs7068124 (p = 0.004), rs3814634 (p = 0.032) and rs10905928 (p = 0.044), and two in TIA1, rs2592178 (p = 0.005) and rs13402990 (p = 0.018) were independently associated with ARDS. In the non-Hispanic Caucasian group, a single variant in CELF2, rs2277212 (p = 0.014), was associated with increased risk of developing ARDS.

Conclusions: The data indicate that SNPs in CELF2 may be associated with the risk of developing ARDS in both African American and non-Hispanic Caucasian children with pneumonia and suggest that the potential role of the splicing factor CELF2 in ARDS should be explored further.
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http://dx.doi.org/10.1186/s13054-016-1454-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011993PMC
September 2016

Genetic and epigenetic factors in the regulation of the immune response.

Curr Opin Pediatr 2016 06;28(3):281-6

Department of Pediatrics and Communicable Diseases, Division of Pediatric Critical Care Medicine, University of Michigan Medical School, Michigan, USA.

Purpose Of Review: The review will update readers on research examining the influence of genetic variation and epigenetics on the immune system and whether genetic variation influences the outcome of critically ill children.

Recent Findings: Although there have been few recent studies examining the role of genetic variation in the severity of disease or outcome in critically ill children, studies in critically ill adults have been informative. For example, genetic variations in the genes coding for various components of the immune response, such as the Toll-like receptor 1, interleukin-1RA, proprotein convertase subtilisin/kexin type 9, adoponectin, nuclear factor erythroid 2-related factor 2, elafin, sphingosine 1-phosphate receptor 3, and sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 have been associated with various outcomes in critically ill adult populations. Many of the variants demonstrate functional consequences in the protein levels or activities. In critically ill children, there is an association with increased ICU length of stay in children with septic shock with one of the Toll-like receptor 1 variants.

Summary: The degree of influence of host genetic variation in the outcome in critically ill children remains a much understudied area of research. However, it remains important because it may not only help identify children at risk for worse outcomes but it may provide insight into mechanisms of critical illnesses and novel therapies.
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http://dx.doi.org/10.1097/MOP.0000000000000356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508538PMC
June 2016

Pathobiology of acute respiratory distress syndrome.

Pediatr Crit Care Med 2015 Jun;16(5 Suppl 1):S6-22

1Division of Critical Care, Department of Pediatrics, University of California, San Francisco, San Francisco, CA. 2Pediatric Intensive Care Unit, Department of Medicine, Children's Hospital, Oakland, CA. 3Division of Pediatric Critical Care, Research Center Oakland, Oakland, CA. 4Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

The unique characteristics of pulmonary circulation and alveolar-epithelial capillary-endothelial barrier allow for maintenance of the air-filled, fluid-free status of the alveoli essential for facilitating gas exchange, maintaining alveolar stability, and defending the lung against inhaled pathogens. The hallmark of pathophysiology in acute respiratory distress syndrome is the loss of the alveolar capillary permeability barrier and the presence of protein-rich edema fluid in the alveoli. This alteration in permeability and accumulation of fluid in the alveoli accompanies damage to the lung epithelium and vascular endothelium along with dysregulated inflammation and inappropriate activity of leukocytes and platelets. In addition, there is uncontrolled activation of coagulation along with suppression of fibrinolysis and loss of surfactant. These pathophysiological changes result in the clinical manifestations of acute respiratory distress syndrome, which include hypoxemia, radiographic opacities, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. Resolution of acute respiratory distress syndrome involves the migration of cells to the site of injury and re-establishment of the epithelium and endothelium with or without the development of fibrosis. Most of the data related to acute respiratory distress syndrome, however, originate from studies in adults or in mature animals with very few studies performed in children or juvenile animals. The lack of studies in children is particularly problematic because the lungs and immune system are still developing during childhood and consequently the pathophysiology of pediatric acute respiratory distress syndrome may differ in significant ways from that seen in acute respiratory distress syndrome in adults. This article describes what is known of the pathophysiologic processes of pediatric acute respiratory distress syndrome as we know it today while also presenting the much greater body of evidence on these processes as elucidated by adult and animal studies. It is also our expressed intent to generate enthusiasm for larger and more in-depth investigations of the mechanisms of disease and repair specific to children in the years to come.
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http://dx.doi.org/10.1097/PCC.0000000000000431DOI Listing
June 2015

Comorbidities and assessment of severity of pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference.

Pediatr Crit Care Med 2015 Jun;16(5 Suppl 1):S41-50

1Division of Pediatric Critical Care, Department of Medicine, Children's Hospital & Research Center Oakland, Oakland, CA. 2Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI. 3Division of Critical Care, Department of Pediatrics, University of California San Francisco, San Francisco, CA. 4Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI.

Objectives: To determine the impact of patient-specific and disease-related characteristics on the severity of illness and on outcome in pediatric patients with acute respiratory distress syndrome with the intent of guiding current medical practice and identifying important areas for future research.

Design: Electronic searches of PubMed, EMBASE, Web of Science, Cochrane, and Scopus were conducted. References were reviewed for relevance and features included in the following section.

Settings: Not applicable.

Subjects: PICU patients with evidence of acute lung injury, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Interventions: Not applicable.

Measurements And Main Results: The comorbidities associated with outcome in pediatric acute respiratory distress syndrome can be divided into 1) patient-specific factors and 2) factors inherent to the disease process. The primary comorbidity associated with poor outcome is preexisting congenital or acquired immunodeficiency. Severity of disease is often described by factors identifiable at admission to the ICU. Many measures that are predictive are influenced by the underlying disease process itself, but may also be influenced by nutritional status, chronic comorbidities, or underlying genetic predisposition. Of the measures available at the bedside, both PaO2/FIO2 ratio and oxygenation index are fairly consistent and robust predictors of disease severity and outcomes. Multiple organ system dysfunction is the single most important independent clinical risk factor for mortality in children at the onset of acute respiratory distress syndrome.

Conclusions: The assessment of oxygenation and ventilation indices simultaneously with genetic and biomarker measurements holds the most promise for improved risk stratification for pediatric acute respiratory distress syndrome patients in the very near future. The next phases of pediatric acute respiratory distress syndrome pathophysiology and outcomes research will be enhanced if 1) age group differences are examined, 2) standardized datasets with adequately explicit definitions are used, 3) data are obtained at standardized times after pediatric acute respiratory distress syndrome onset, and 4) nonpulmonary organ failure scores are created and implemented.
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http://dx.doi.org/10.1097/PCC.0000000000000430DOI Listing
June 2015

The outcomes of children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference.

Pediatr Crit Care Med 2015 Jun;16(5 Suppl 1):S118-31

1Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI. 2Division of Pediatric Critical Care Medicine, Department of Pediatrics, Cruces University Hospital, Bizkaia, Spain. 3Division of Pediatric Critical Care, Department of Pediatrics, Universite de Sherbrooke, Sherbrooke, QC, Canada. 4Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington and Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA.

Objective: To provide additional details and evidence behind the recommendations for outcomes assessment of patients with pediatric acute respiratory distress syndrome from the Pediatric Acute Lung Injury Consensus Conference.

Design: Consensus conference of experts in pediatric acute lung injury.

Methods: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The outcomes subgroup comprised four experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used.

Results: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, seven of which related to outcomes after pediatric acute respiratory distress syndrome. All seven recommendations had strong agreement. Children with acute respiratory distress syndrome continue to have a high mortality, specifically, in relation to certain comorbidities and etiologies related to pediatric acute respiratory distress syndrome. Comorbid conditions, such as an immunocompromised state, increase the risk of mortality even further. Likewise, certain etiologies, such as non-pulmonary sepsis, also place children at a higher risk of mortality. Significant long-term effects were reported in adult survivors of acute respiratory distress syndrome: diminished lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive function. Little knowledge of long-term outcomes exists in children who survive pediatric acute respiratory distress syndrome. Characterization of the longer term consequences of pediatric acute respiratory distress syndrome in children is vital to help identify opportunities for improved therapeutic and rehabilitative strategies that will lessen the long-term burden of pediatric acute respiratory distress syndrome and improve the quality of life in children.

Conclusions: The Consensus Conference developed pediatric-specific recommendations for pediatric acute respiratory distress syndrome regarding outcome measures and future research priorities. These recommendations are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.
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http://dx.doi.org/10.1097/PCC.0000000000000438DOI Listing
June 2015

Lack of association of the caspase-12 long allele with community-acquired pneumonia in people of African descent.

PLoS One 2014 26;9(2):e89194. Epub 2014 Feb 26.

Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Community-acquired pneumonia (CAP) is a common cause of sepsis. Active full-length caspase-12 (CASP12L), confined to the people of African descent, has been associated with increased susceptibility to and mortality from severe sepsis. The objective of this study was to determine whether CASP12L was a marker for susceptibility and/or severity of CAP. We examined three CAP cohorts and two control populations: 241 adult Memphis African American CAP patients, 443 pediatric African American CAP patients, 90 adult South African CAP patients, 120 Memphis healthy adult African American controls and 405 adult Chicago African American controls. Clinical outcomes including mortality, acute respiratory distress syndrome (ARDS), septic shock or severe sepsis, need for mechanical ventilation, and S. pneumoniae bacteremia. Neither in the three individual CAP cohorts nor in the combined CAP cohorts, was mortality in CASP12L carriers significantly different from that in non-CASP12L carriers. No statistically significant association between genotype and any measures of CAP severity was found in any cohort. We conclude that the functional CASP12L allele is not a marker for susceptibility and/or severity of CAP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935862PMC
January 2015

Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia*.

Crit Care Med 2012 Nov;40(11):3042-9

Section of Pulmonary and Sleep Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Objectives: The cystic fibrosis transmembrane conductance regulator regulates fluid balance in alveolar epithelial cells and appears to modulate the inflammatory response. To determine whether more severe lung injury in children who develop community-acquired pneumonia is associated with variations known to affect function in the gene coding for cystic fibrosis transmembrane conductance regulator.

Design: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia.

Setting: Three major tertiary care children's hospitals.

Subjects: Caucasian and African American children with community-acquired pneumonia either evaluated in the emergency department or admitted to the hospital.

Interventions: None.

Measurements And Main Results: Caucasian and African American children with pneumonia were genotyped for the most common variants reported to affect cystic fibrosis transmembrane conductance regulator function, the p.508del mutation, the (TG)mTn variable repeat region, and the M470V polymorphism in the cystic fibrosis transmembrane conductance regulator gene. Genotypes and haplotypes were determined, and the association of high-risk alleles or high-risk haplotypes (defined as the presence of at least one variant known to decrease the level of functional cystic fibrosis transmembrane conductance regulator) with the need for mechanical ventilation or the development of acute lung injury was evaluated. Forty-two children in the Caucasian cohort (n = 304) required mechanical ventilation; 32 developed acute lung injury. Forty-three children in the African American cohort (n = 474) required mechanical ventilation; 29 developed acute lung injury. In African American children, high-risk (TG)mTn alleles known to result in decreased levels of functional cystic fibrosis transmembrane conductance regulator were associated with the need for mechanical ventilation (p = .0013) and the development of acute lung injury (p = .0061). Multivariable analysis demonstrated that high-risk (TG)mTn alleles were independently associated with mechanical ventilation (odds ratios = 3.19; 95% confidence interval, 1.63-6.26) and acute lung injury (odds ratios = 3.36; 95% confidence interval, 1.50-7.53) in African American children.

Conclusion: Genetic variation in cystic fibrosis transmembrane conductance regulator is associated with acute lung injury in African American children with community-acquired pneumonia.
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http://dx.doi.org/10.1097/CCM.0b013e31825d8f73DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273667PMC
November 2012

MAPK and JAK-STAT signaling pathways are involved in the oxidative stress-induced decrease in expression of surfactant protein genes.

Cell Physiol Biochem 2012 25;30(2):334-46. Epub 2012 Jun 25.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53201, USA.

Oxidative stress is generated by reactive oxygen species (ROS) including hydrogen peroxide (H(2)O(2)), hydroxyl radical (•OH ) and superoxide anion (O(2--)), which are produced as by-products of cellular metabolism. An imbalance in cellular redox status is a potent pathogenic factor that contributes to various chronic inflammatory diseases. In this study, we demonstrate that H(2)O(2 )decreases surfactant protein A, B and ABCA3 mRNA level, and increases SP-D mRNA level in human pulmonary lung epithelial cells. The decreased mRNA level of SP-A and SP-B were significant with a maximum inhibition of 79 and 87%, respectively by 150 µM H(2)O(2 )after 24 hrs of incubation. In addition, ABCA3 mRNA level was decreased with a maximum inhibition of 55% by 150 µM H(2)O(2 )after 12 hrs of incubation. In contrast, 150 µM H(2)O(2 )caused the SP-D mRNA level to increase to 200% of control after 8 hrs of incubation. The H(2)O(2)-induced gene repression or activation of SP-A, SP-B, SP-D and ABCA3 was blocked by pretreatment with the antioxidants N-acetyl-L-cysteine (NAC) and catalase. Furthermore, the inhibition of SP-A and SP-B was associated with reduced thyroid transcription factor -1 (TTF-1) DNA binding activity, and this reduced TTF-1 binding activity may be due to decreased TTF-1 protein expression level. The analyses of signal transduction pathways that may play a role in the regulation of gene expression by H(2)O(2 )using several specific inhibitors showed that U0126, an inhibitor of ERK1/2 upstream kinase MEK1/2, blocked both H(2)O(2)-induced inhibition of SP-A and SP-B gene expression, whereas SB203580, an inhibitor of p38 MAPK, partially blocked H(2)O(2)-mediated inhibition of SP-A gene expression but not SP-B expression. In contrast, AG-490, a specific inhibitor of JAK-STAT pathway, blocked H(2)O(2)-mediated inhibition of SP-B gene expression but not SP-A expression. Immunoblot analyses using specific phosphor-antibodies demonstrated that ERK1/2, p38 MAPK and STAT3 are phosphorylated by oxidative stress suggesting that H(2)O(2)-induced inhibition of SP-A and SP-B gene expression is associated with MAPK and JAKSTAT signaling pathway. These data, therefore, suggest that H(2)O(2 )affects SP-A and SP-B gene regulation by reducing TTF-1 DNA binding activity via MAPKs or STAT signaling pathways.
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http://dx.doi.org/10.1159/000339068DOI Listing
November 2012

Association of IL-1β -511 polymorphism with severe veno-occlusive disease in pediatric-matched allogeneic hematopoietic stem cell transplantation.

J Pediatr Hematol Oncol 2012 Apr;34(3):175-9

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.

Single nucleotide polymorphisms (SNPs) of the interleukin 1 (IL-1) family have been implicated in acute graft-versus-host disease and mortality postallogeneic hematopoietic stem cell transplantation (HSCT) in adults. Hepatic veno-occlusive disease (VOD) is a well-known complication of HSCT and can result in an increased risk of mortality. In this study, we sought to investigate the association of both patient and donor genotypes at the IL-1β -511 cytidine/thymidine (C/T) polymorphic site with hepatic VOD and mortality in an exclusive pediatric cohort undergoing matched myeloablative allogeneic HSCT. Donor TT genotype was associated with higher cumulative incidence of grade III-IV hepatic VOD at 3 months after transplantation relative to donor CT and CC genotypes (25±13.1% in TT, 2.9±2.9% in CT, and 3.6±3.6% in CC; P=0.024). Neither recipient nor donor IL-1β -511 single nucleotide polymorphisms genotypes were associated with mortality or relapse. Our findings suggest that donor, rather than host, genotype at the IL-1β -511 polymorphic site may associate with higher risk for severe VOD after matched allogeneic HSCT. Our findings challenge the assumption that host factors are exclusively responsible for VOD and suggest a novel role for the donor inflammasome pathway in inducing injury and microvascular disease after HSCT, which merits further study in a larger cohort analysis.
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http://dx.doi.org/10.1097/MPH.0b013e3182427575DOI Listing
April 2012

Alpha-adrenergic receptor gene polymorphisms and cardiovascular reactivity to stress in Black adolescents and young adults.

Psychophysiology 2012 Mar 14;49(3):401-12. Epub 2011 Nov 14.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38104, USA.

Cardiovascular reactivity to stress and α-adrenergic receptor (α-AR) function may contribute to the development of hypertension. As Black Americans have an increased risk of hypertension, we evaluated associations between α(1A) -AR (Arg492Cys), α(2A) -AR (-1291C/G), and α(2B) -AR (Ins/Del301-303) gene variants and cardiovascular reactivity in 500 normotensive Black youth. Heart rate, preejection period, total peripheral resistance, and blood pressure were measured during cold and psychological stress. The Arg492Cys polymorphism in the α(1A) -AR gene was associated with heart rate reactivity to stress, but the association depended on sex. The -1291C/G promoter polymorphism in the α(2A) -AR gene was associated with vascular reactivity to stress; vasoconstriction increased as a linear function of the number of copies of the variant G allele. Thus, specific associations emerged between genetic variations in α-Ars and cardiovascular reactivity in young Blacks.
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http://dx.doi.org/10.1111/j.1469-8986.2011.01319.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275673PMC
March 2012

Racial disparities in pediatric intensive care unit admissions.

South Med J 2011 Sep;104(9):640-6

Division of Pediatric Critical Care, University of Kentucky College of Medicine, KY, USA.

Objectives: Racial disparities in therapies and outcomes in adult and neonatal ICUs are well documented; however, little is known regarding racial disparities in pediatric intensive care unit (PICU). Our objective was to determine whether racial disparities exist in the admission of critically ill children to the PICU.

Methods: We retrospectively analyzed admissions to a PICU in a tertiary care pediatric hospital. Summarized demographic data was analyzed from the county health department.

Results: Of the 4676 admissions to the PICU between January 1, 1997 and December 31, 1999, 1030 children were <48 months of age, lived in Shelby County, TN, and were either African American (789, 76.6%) or non-Hispanic white (241, 23.4%). The surrounding county was comprised of approximately 58% African American and 41% non-Hispanic white children ≤ 48 months of age. A history of premature birth was more common in African American children than non-Hispanic white children (46.8% vs. 32.8%; P < 0.0001). Mortality was 5.7% overall and was not significantly different between African Americans and non-Hispanic whites but was higher for those children with a history of premature birth (4.6% vs. 7.1%, P < 0.026). The overall relative risk of admission to the PICU for African American children was 2.12 (95% CI, 1.66-2.74), for African American children with a history of premature birth was 1.44 (95% CI, 0.96-2.21), and for full-term African American children was 1.82 (95% CI, 1.33 -2.49).

Conclusions: Racial differences in admission to the PICU exist with African American children having a greater risk for PICU admission than non-Hispanic white children.
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http://dx.doi.org/10.1097/SMJ.0b013e3182296e52DOI Listing
September 2011

Role of angiotensin-converting enzyme gene polymorphism in persistent pulmonary hypertension of the newborn.

Acta Paediatr 2011 Oct 8;100(10):1326-30. Epub 2011 Apr 8.

Department of Pediatrics, Wayne State University, Children's Hospital of Michigan, Detroit, MI 48201, USA.

Aim: To evaluate the association of angiotensin-converting enzyme (ACE) gene polymorphism with risk/severity of persistent pulmonary hypertension of the newborn (PPHN) among at risk infants.

Methods: Infants ≥ 34 weeks with respiratory distress at birth were recruited. PPHN was diagnosed clinically and by cardiac echocardiogram. Control group consisted of infants with respiratory distress who did not develop PPHN. ACE genotyping (DD, II, DI genotypes) and serum ACE levels were determined.

Results: A total of 120 infants were included (PPHN = 44; control = 76). Frequency of ACE DD genotype was not different between the two groups of infants (25% versus 33%). Among PPHN infants, severity of illness did not differ between genotypes. Mean (SD) serum ACE levels [15 (9) versus 24 (13) versus 29 (14) U/L] were positively associated with the number of D alleles and inversely associated with infants' gestational age (GA) and level of cardiovascular support.

Conclusion: Angiotensin-converting enzyme gene polymorphism did not impact the risk or severity of PPHN among infants ≥ 34 weeks GA.
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http://dx.doi.org/10.1111/j.1651-2227.2011.02277.xDOI Listing
October 2011

The influence of genetic variation in surfactant protein B on severe lung injury in African American children.

Crit Care Med 2011 May;39(5):1138-44

Division of Pediatric Critical Care, Medical College of Wisconsin and the Children's Research Institute, Milwaukee, WI, USA.

Objective: To determine whether genetic variations in the gene coding for surfactant protein B are associated with lung injury in African American children with community-acquired pneumonia.

Design: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia.

Setting: Two major tertiary care children's hospitals.

Subjects: African American children with community-acquired pneumonia (n = 395) either evaluated in the emergency department or admitted to the hospital.

Interventions: None.

Measurements And Main Results: Three hundred ninety-five African American children (14 days to 18 yrs of age) with community-acquired pneumonia were enrolled. Thirty-seven patients required mechanical ventilation and 26 of these were diagnosed with acute lung injury or acute respiratory distress syndrome. Genotyping was performed on seven linkage disequilibrium-tag single nucleotide polymorphisms in the surfactant protein B gene. Univariate analysis demonstrated two linkage disequilibrium-tag single nucleotide polymorphisms, rs1130866 (also known as SP-B + 1580 C/T) and rs3024793, were associated with the need for mechanical ventilation in African American children (p = .016 and p = .030, respectively). Multivariable analysis indicated that both of these single nucleotide polymorphisms are independently associated with need for mechanical ventilation (p = .040 and p = .012, respectively) as was rs7316 when its interaction with age was considered (p = .015). Multivariable analysis examining acute lung injury demonstrated a significant association of rs7316 with acute lung injury (p = .031). Haplotype analysis was also performed. Two haplotypes, GTGCGCG and ATATAAG, were associated with need for mechanical ventilation using either univariate (p = .041 and p = .043, respectively) or multivariable analysis (odds ratios of 2.62, p = .048, and 3.12, p = .033, respectively).

Conclusions: Genetic variations in the gene coding for surfactant protein B are associated with more severe lung injury as indicated by the association of specific single nucleotide polymorphism genotypes and haplotypes with the need for mechanical ventilation in African American children with community-acquired pneumonia.
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http://dx.doi.org/10.1097/CCM.0b013e31820a9416DOI Listing
May 2011

Beta-adrenergic receptor gene polymorphisms and cardiovascular reactivity to stress in Black adolescents and young adults.

Psychophysiology 2010 Sep 2;47(5):863-73. Epub 2010 Apr 2.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.

Cardiovascular reactivity to stress and beta-adrenergic receptor (beta-AR) function may contribute to the development of hypertension. As Black Americans have an increased risk of hypertension, we evaluated associations between beta(1)-AR (Arg389Gly) and beta(2)-AR (Arg16Gly, Gln27Glu) gene variants and cardiovascular reactivity in 500 Black youth. Heart rate, preejection period, total peripheral resistance, and blood pressure reactivity were measured during cold and psychological stress. The Arg389Gly polymorphism in the beta(1)-AR was associated with preejection period reactivity in males but not in females. The Arg16Gly polymorphism in the beta(2)-AR was associated with diastolic blood pressure reactivity only during video game stress. An association between the Gln27Glu polymorphism in the beta(2)-AR and vascular reactivity depended on sex. Thus, specific patterns of associations emerged between genetic variations in beta-ARs and cardiovascular reactivity in young Blacks.
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http://dx.doi.org/10.1111/j.1469-8986.2010.01006.xDOI Listing
September 2010

Genetic variation in MYLK and lung injury in children and adults with community-acquired pneumonia.

Pediatr Crit Care Med 2010 Nov;11(6):731-6

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Objective: To investigate whether selected single nucleotide polymorphisms in the myosin light chain kinase gene are associated with more severe lung injury in children and adults with community-acquired pneumonia. Previous studies have demonstrated an association between single nucleotide polymorphisms in the myosin light chain kinase gene and increased severity of acute lung injury in adults.

Design: Prospective, case-control genetic association study.

Setting: Three tertiary children's hospitals and one adult healthcare system.

Patients: A total of 800 pediatric patients and 393 adult patients.

Interventions: None.

Measurements And Main Results: Genetic variation in the myosin light chain kinase gene was examined. The pediatric cohort was predominantly composed of African American (n = 443) and Caucasian (n = 253) children. A total of 393 patients made up the adult cohort. Within the pediatric cohort, single nucleotide polymorphisms rs16834493, rs820463, and rs9840993 were genotyped in the African American patients, whereas single nucleotide polymorphisms rs960224, rs33264, rs11718105, and rs9289225 were genotyped in the Caucasian patients. One single nucleotide polymorphism (rs820336) was genotyped in both groups. Genotyping in the adult cohort included rs820336, rs860224, rs33264, and rs11718105. Genotyping was performed using the Taqman Assay. Data were analyzed separately for African Americans and Caucasians and for children and adults. No associations were observed between the myosin light chain kinase gene single nucleotide polymorphisms genotyped in children with community-acquired pneumonia and increased severity of lung injury. Similarly, no associations were observed between myosin light chain kinase gene single nucleotide polymorphisms genotyped in adults with community-acquired pneumonia and increased severity of lung injury.

Conclusions: No association between the selected single nucleotide polymorphisms in the myosin light chain kinase gene and either the need for positive-pressure ventilation or the development of acute lung injury/acute respiratory distress syndrome was observed in children with community-acquired pneumonia. This suggests that variation in this gene may play less of a role in lung injury in children or adults with community-acquired pneumonia than in adults with sepsis or trauma.
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http://dx.doi.org/10.1097/PCC.0b013e3181ce7497DOI Listing
November 2010

Surfactant protein A2 polymorphisms and disease severity in a respiratory syncytial virus-infected population.

J Pediatr 2010 Mar 14;156(3):409-14. Epub 2009 Nov 14.

Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital for Children, Boston, MA 02114, USA.

Objective: To examine whether genetic variations within the surfactant protein A2 (SP-A2) gene are associated with respiratory syncytial virus (RSV) disease severity in infected children.

Study Design: Naturally infected children aged < or =24 months were prospectively enrolled in 3 RSV seasons. SP-A2 genotyping was performed. Independent clinical predictors of disease severity were analyzed. The association of SP-A2 genetic diversity and disease severity was tested by using multivariate logistic regression models and 4 levels of disease gradation as outcome measures.

Results: Homozygosity of the 1A(0) allele was protective against hospitalization (odds ratio [OR] = 0.15, P = .0010). This remained significant in African American patients (OR = 0.24, P = .042) and Caucasian patients (OR = 0.05, P = .021) after adjustment for other co-variates. Hospitalized children with the 1A(2) allele demonstrated significant protection from severe disease with univariate analyses, but only a trend for protection with multivariate analyses. Patients homozygous or heterozygous for an asparagine at amino acid position 9 were twice or more likely to need intensive care unit admission (OR = 2.15, P = .022), require intubation (OR = 3.04, P = .005), and have a hospitalization lasting > or =4 days (OR = 1.89, P = .02) compared with children homozygous for a threonine at this position.

Conclusions: SP-A2 polymorphisms are associated with the severity of RSV infection in infants.
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http://dx.doi.org/10.1016/j.jpeds.2009.09.043DOI Listing
March 2010

Identification and characterization of a novel ABCA3 mutation.

Physiol Genomics 2010 Jan 27;40(2):94-9. Epub 2009 Oct 27.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53201, USA.

Mutations in the gene coding for ATP-binding cassette protein A3 (ABCA3) are recognized as a genetic cause of lung disease of varying severity. Characterization of a number of mutant ABCA3 proteins has demonstrated that the mutations generally affect intracellular localization or the ability of the protein to hydrolyze ATP. A novel heterozygous mutation that results in the substitution of cysteine for arginine at amino acid 295 in ABCA3 was identified in a premature infant with chronic respiratory insufficiency and abnormal lamellar bodies. Sequencing of DNA performed in study participants demonstrated that this was a mutation and not a common variant. Plasmid vectors containing ABCA3 with the identified novel mutation tagged with green fluorescent protein on the carboxy terminus were generated. The effect of the mutation on protein function was characterized by examining the glycosylation state of the mutant protein in transiently transfected HEK293 cells and by examining ATP hydrolysis activity of the mutant protein with a vanadate-induced nucleotide trapping assay in stably transfected HEK293 cells. The ABCA3 protein containing the R295C mutation undergoes normal glycosylation and intracellular localization but has dramatically reduced ATP hydrolysis activity (12% of wild type). The identification of one copy of this novel mutation in a premature infant with chronic respiratory insufficiency suggests that ABCA3 haploinsufficiency together with lung prematurity may result in more severe, or more prolonged, respiratory failure.
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http://dx.doi.org/10.1152/physiolgenomics.00123.2009DOI Listing
January 2010

Profiling pediatric sepsis.

Crit Care Med 2009 May;37(5):1795-6

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http://dx.doi.org/10.1097/CCM.0b013e3181a1a220DOI Listing
May 2009

Interleukin-1 receptor antagonist intron 2 variable number of tandem repeats polymorphism and respiratory failure in children with community-acquired pneumonia.

Pediatr Crit Care Med 2008 Nov;9(6):553-9

Department of Pediatrics, Division of Critical Care, Children's Memorial Hospital, Northwestern University, Evanston, IL, USA.

Objective: To determine whether the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene is associated with lung injury in children with community-acquired pneumonia.

Design: A prospective cohort of children diagnosed with community-acquired pneumonia.

Setting: Two pediatric hospitals.

Patients: Eight hundred fifty pediatric patients with community-acquired pneumonia were enrolled.

Interventions: Genotyping of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene was performed on DNA isolated from whole blood.

Measurements And Main Results: The requirement for positive pressure ventilation or the diagnosis of acute lung injury or acute respiratory distress syndrome were the main outcomes of the study. Children (14 days-19 yrs) with community-acquired pneumonia (850) were enrolled; analysis was limited to African American (515) and Caucasian (232) patients. Of the 82 patients requiring positive pressure ventilation, 44 were diagnosed with acute lung injury or acute respiratory distress syndrome. Multivariate logistic regression analyses indicated that children without a copy of the A1 allele of the variable nucleotide tandem repeat polymorphism in intron 2 of the interleukin-1 receptor antagonist gene were more likely to need positive pressure ventilation compared to those with one or two copies of this allele (odds ratio = 2.65, confidence interval, 1.02-6.90). In addition, the absence of the A1 allele also appeared to be associated with the development of community-acquired pneumonia-induced acute lung injury/acute respiratory distress syndrome (odds ratio = 3.1, confidence interval, 0.99-9.67).

Conclusions: In children with community-acquired pneumonia, absence of the A1 allele at the interleukin-1 receptor antagonist intron 2 polymorphic site is associated with increased risk for more severe lung injury, as measured by the need for positive pressure ventilation or the development of acute lung injury or acute respiratory distress syndrome. Conversely, presence of the A1 allele is associated with decreased risk for more severe lung injury in this patient population.
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http://dx.doi.org/10.1097/PCC.0b013e31818d32f1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760301PMC
November 2008