Michael W. Quasney

Association between surfactant protein B + 1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia.

Objective:Pulmonary surfactant protein (SP)-B plays a vital role in the formation and function of surfactant in the lung. A genetic polymorphism (SP-B + 1580) is postulated to result in diminished activity of SP-B. The objective was to determine whether the SP-B + 1580 CC genotype is associated with an increased risk of respiratory failure and ARDS in adults with community-acquired pneumonia. Design:Prospective cohort of adults diagnosed with community-acquired pneumonia. Setting:Hospital system. Patients:We enrolled 402 adults ≥18 yrs of age with community-acquired pneumonia; 158 were white, 243 were African American, and one was Asian. Interventions:Genotypic analysis was performed on DNA isolated from whole blood using polymerase chain reaction amplification and DdeI restriction enzyme digestion. Measurements and Main Results:We recorded the requirement for mechanical ventilation, the presence of acute respiratory distress syndrome (ARDS) or septic shock, and mortality. Sixty-three patients required mechanical ventilation, 12 patients developed ARDS, and 35 patients developed septic shock. Genotypic frequencies at the SP-B+1580 site were T/T 183 of 402 (0.45), T/C 160 of 402 (0.40), and C/C 59 of 402 (0.15). Of the 59 patients who were C/C at the SP-B + 1580 site, 21 (0.356) required mechanical ventilation, compared with 26 of 160 patients (0.163) who were T/C and 16 of 183 (0.087) patients who were T/T (p < .001). ARDS developed in five of 59 (0.085) patients with the C/C genotype, compared with six of 160 (.038) patients with T/C and one of 183 patients with T/T (0.005, p < .009). Septic shock occurred in 12 of 59 (0.203) patients with the C/C genotype, compared with 13 of 160 (0.081) patients with T/C and ten of 183 (0.055) patients with T/T (p < .001). Mortality rate was not different between the three genotypes. Conclusion:Carriage of the C allele at the SP-B + 1580 site is associated with ARDS, septic shock, and the need for mechanical ventilation in adults with community-acquired pneumonia.

Genetic polymorphisms in sepsis

Context: Wide variability exists in the susceptibility to and outcome from sepsis even within similar intensive care unit populations. Some of this variability in the host may be due to genetic variation in genes coding for components of the innate immune response. Objective: To review the evidence for a genetic influence on the susceptibility to and outcome from sepsis. Design: Literature review. Patients: Variety of adult and pediatric patients with various critical illnesses and infections. Interventions: None. Main Outcome Measures: Susceptibility to clinical symptoms of sepsis and outcome as measured by severity of disease and mortality. Results: Polymorphisms in genes coding for proteins involved in the recognition of bacterial pathogens (Toll-like receptor 4, CD14, Fc&ggr;RIIa, and mannose-binding lectin) and the response to bacterial pathogens (tumor necrosis factor-&agr;, interleukin (IL)-1&agr;, IL-1&bgr;, IL-1 receptor agonist, IL-6, IL-10, heat shock proteins, angiotensin I converting enzyme, plasminogen activator inhibitor-1) can influence the amount or function of the protein produced in response to bacterial stimuli. Evidence is discussed suggesting that some of these genetic polymorphisms influence the susceptibility to and outcome from sepsis. Conclusion: Host genetic variability in the regulatory and coding regions of genes for components of the innate immune system may influence the susceptibility to and/or outcome from sepsis. The disparate results observed in many studies of polymorphisms in sepsis emphasize the need for future studies to be larger, to include the analysis of multiple polymorphisms, and to be better designed with respect to control populations to identify the degree of influence that genetic variability has on sepsis.

Heat shock protein 70-2+1267 AA homozygotes have an increased risk of septic shock in adults with community-acquired pneumonia

ObjectiveHeat shock protein (HSP)70-2 is an important immunomodulatory protein induced in response to inflammatory stimuli. We assessed whether HSP70-2+1267 genotype influenced the risk of septic shock in a prospective cohort study of community-acquired pneumonia and whether HSP70-2+1267 genotype is a better predictor of septic shock than the genotype at lymphotoxin-&agr; +250. DesignProspective cohort study. SettingA large, nonprofit, private hospital system in Memphis, TN. PatientsAdults admitted with community-acquired pneumonia between 1998 and 2001. Septic shock was defined according to consensus criteria (American College of Chest Physicians/Society of Critical Care Medicine, 1992). InterventionsBlood sampling. Measurements and Main ResultsA total of 343 subjects were enrolled; 30 had septic shock. HSP70-2+1267 and lymphotoxin-&agr; +250 genotype was determined using polymerase chain reaction and restriction enzyme digestion. HSP70-2+1267 AA genotype was the strongest predictor of septic shock (p = .0005; relative risk, 3.5). Lymphotoxin-&agr; +250 AA genotype was also associated with an increased risk of septic shock (p = .002; relative risk, 2.7). Logistic regression analysis found only age (p = .04) and HSP70-2+1267 genotype (p = .006) were predictors of septic shock. The greatest risk of septic shock was associated with carriage of the HSP70-2+1267 A/lymphotoxin-&agr; +250 A haplotype (p < .0001). ConclusionsHSP70-2+1267 genotype is a stronger predictor of septic shock in patients with community-acquired pneumonia than lymphotoxin-&agr; +250 genotype.

Increased frequency of alleles associated with elevated tumor necrosis factor-α levels in children with Kawasaki disease

Genetic polymorphisms influence the magnitude of the cytokine response after an inflammatory stimulus. To determine whether such polymorphisms might play a role in Kawasaki disease (KD), we analyzed white and Japanese children with KD and control populations for two polymorphic loci in which the A allele is associated with high tumor necrosis factor-α secretion. The lymphotoxin-α+250 A/A genotype was overrepresented among white children with KD compared with controls (0.59 versus 0.36;p = 0.013). The tumor necrosis factor-α−308 A/G genotype was overrepresented among whites with KD who had coronary artery abnormalities compared with those with normal echocardiograms (0.36 versus 0.09;p = 0.044). No significant difference was seen at either locus between Japanese children with KD and Japanese controls. The increased frequency of the high secretor alleles in white children with KD suggests that these loci may be related to susceptibility to KD and to outcome after disease.

Increased frequency of the tumor necrosis factor-α-308 a allele in adults with human immunodeficiency virus dementia

Genetic polymorphisms in the regulatory regions of various cytokine genes influence the amount of cytokine produced in response to inflammatory stimuli. To determine whether such polymorphisms might play a role in human immunodeficiency virus (HIV) dementia, a disease process in which tumor necrosis factor (TNF)‐α is believed to play a role, we analyzed HIV‐infected adults with and without dementia and control populations for a polymorphic site located in the promoter region of the gene coding for TNF‐α. The presence of the A allele at the TNF‐α‐308 site was overrepresented among adults with HIV dementia compared to those without dementia (0.28 versus 0.07; OR 5.5; 95% CI 1.8–17.0) and a healthy control population (0.28 versus 0.11). The increased frequency of the A allele in HIV‐infected adults with dementia suggests that this locus may play a role in the pathophysiology of dementia and suggests a genetic predisposition for the development of HIV dementia.

Plastic bronchitis occurring late after the Fontan procedure : Treatment with aerosolized urokinase

Objective To describe the use of aerosolized urokinase in a patient with plastic bronchitis after a Fontan procedure. Design Case report. Setting Pediatric intensive care unit in a university-affiliated children’s hospital. Patients Report of one patient with acute respiratory failure secondary to plastic bronchitis. Interventions Aerosolized urokinase, multiple bronchoscopies, corticosteroids, mucolytics, bronchodilators, and atrial pacing. Measurements and Main Results Airway obstruction secondary to recurring casts improved with the treatments. Histologic analysis of the casts demonstrated less fibrin after treatments with aerosolized urokinase. No adverse events were noted. Conclusions The addition of aerosolized urokinase to this patient’s treatment regimen helped to resolve life-threatening airway obstruction secondary to fibrin casts.

A Region of the Third Intracellular Loop of the Short Form of the D2 Dopamine Receptor Dictates Gi Coupling Specificity

The D2 dopamine receptor has two isoforms, the short form (D2s receptor) and the long form (D2l receptor), which differ by the presence of a 29-amino acid insert in the third cytoplasmic loop. Both the D2s and D2l receptors have been shown to couple to members of the Gαi family of G proteins, but whether each isoform couples to specific Gαi protein(s) remains controversial. In previous studies using Gαi mutants resistant to modification by pertussis toxin (GαiPT), we demonstrated that the D2s receptor couples selectively to Gαi2PT and that the D2l receptor couples selectively to Gαi3PT (Senogles, S. E. (1994) J. Biol. Chem. 269, 23120–23127). In this study, two point mutations of the D2s receptor were created by random mutagenesis (R233G and A234T). The two mutant D2s receptors demonstrated pharmacological characteristics comparable with those of the wild-type D2s receptor, with similar agonist and antagonist binding affinities. We used human embryonic kidney 293 cells stably transfected with Gαi1PT, Gαi2PT, or Gαi3PT to measure agonist-mediated inhibition of forskolin-stimulated cAMP accumulation before and after pertussis toxin treatment. The two mutant D2s receptors demonstrated a change in Gi coupling specificity compared with the wild-type D2s receptor. Whereas the wild-type D2s receptor coupled predominantly to Gαi2PT, mutant R233G coupled preferentially to Gαi3PT, and mutant A234T coupled preferentially to Gαi1PT. These results suggest that this region of the third cytoplasmic loop is crucial for determining Gi protein coupling specificity.

Tumor Necrosis Factor Gene Polymorphisms and the Variable Presentation and Outcome of Community-Acquired Pneumonia

2002;121;87S-88S Chest William Y. Park, C. W. Frevert, V. A. Wong and T. R. Martin * Phenotypes in 101 Normal Human Subjects High and Low Inflammatory Response http://chestjournal.chestpubs.org/content/121/3_suppl/87S.2.full.html can be found online on the World Wide Web at: The online version of this article, along with updated information and services ) ISSN:0012-3692 http://chestjournal.chestpubs.org/site/misc/reprints.xhtml ( distributed without the prior written permission of the copyright holder. All rights reserved. No part of this article or PDF may be reproduced or College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. has been published monthly since 1935. Copyright2002by the American is the official journal of the American College of Chest Physicians. It Chest

Association of tumor necrosis factor gene polymorphisms and prolonged mechanical ventilation after coronary artery bypass surgery

ObjectiveProlonged mechanical ventilation is a common complication after coronary artery bypass graft surgery. Tumor necrosis factor &agr; is an important proinflammatory mediator in the post–coronary artery bypass graft inflammatory cascade. We attempted to study the effect of polymorphisms at the −308 site in the promoter region of the tumor necrosis factor gene (TNF−308) and the +250 site within the lymphotoxin-&agr; gene (LT&agr;+250) on the risk of prolonged mechanical ventilation after coronary artery bypass grafting. DesignProspective observational study. SettingTertiary care center. PatientsA total of 400 patients undergoing coronary artery bypass grafting were enrolled. MeasurementsThe primary end point was time to extubate. Secondary end points were the percentages of patients extubated at 8, 24, and 48 hrs; the length of intensive care unit and hospital stay; the need for a rehabilitation facility; and 30-day mortality. Precollected blood was used for gene analysis. Genotyping was performed by polymerase chain reaction and restriction enzyme digestion. Main ResultsPatients with an AA genotype at the LT&agr;+250 site and those without the LT&agr;+250G/−308TNFG haplotype had a shorter duration of mechanical ventilation (11.5 vs. 27.8 hrs and 11.2 vs. 29.4 hrs;p = .039 and .01, respectively). The risk of prolonged mechanical ventilation at 8, 24, and 48 hrs was higher for patients with a GA or GG genotype at the LT&agr;+250 site and the LT&agr;+250G/TNF−308G haplotype. This association between genotype and duration of mechanical ventilation was more dramatic in patients undergoing conventional coronary artery bypass grafting than in those undergoing off-pump coronary artery bypass grafting. With Bayesian analysis, clinical criteria and genotype can be used sequentially to predict the risk of prolonged mechanical ventilation. ConclusionsThe LT&agr;+250 and LT&agr;+250G/TNF−308G haplotypes are associated with prolonged mechanical ventilation after coronary artery bypass graft. Preoperative genetic screening may guide intraoperative management to reduce postoperative complications.

Tumor necrosis factor-α allele lymphotoxin-α+250 is associated with the presence and severity of placental inflammation among preterm births

Histologic inflammation of placenta has been associated with increased risk for bronchopulmonary dysplasia and periventricular leukomalacia among preterm infants. Tumor necrosis factor-α (TNF-α) plays a central role in the regulation of inflammation. Some alleles of TNF (LT-α+250, TNF-α−308, and TNF-α −238) have been associated with susceptibility and/or severity of many diseases characterized by inflammation and/or involving the immune system. To determine whether alleles of TNF-α affect the risk and/or the severity of chorioamnionitis, we examined the placentas of 101 preterm births (birth weight ≤1250 g) for the presence of inflammation. Maternal and fetal chorioam-nionitis (MCA and FCA, respectively) were graded for severity and staged for location of inflammatory infiltrate. Analysis for TNF-α alleles was done using PCR-restriction fragment length polymorphism technique on DNA extracted from infants whole blood. MCA and FCA were seen in 45 and 38 placentas, respectively (p = 0.64). Genotypes of TNF-α −308 did not affect the development or the severity of placental inflammation. However, the AA genotype of LT-α+250 occurred more often when MCA and FCA were present compared with placentas without inflammation (p = 0.016 and p = 0.007, respectively). The GA genotype of TNF-α −238 was more common in placentas with severe MCA than with mild MCA (p = 0.015). The number of A alleles of LT-α+250 (GG = 0, GA = 1, AA = 2) correlated directly and significantly with grades and stages of MCA and FCA (p < 0.05). The AA genotype of LT-α +250 is associated with the development of chorioamnionitis among preterm births. The A allele of LT-α+250 seems to worsen the degree of placental inflammation.